CN101541330A

CN101541330A - Use of vitamin D compounds for the prevention of adhesions

Info

Publication number: CN101541330A
Application number: CNA2007800433059A
Authority: CN
Inventors: E·科利; M·马里亚尼; P·帕尼纳
Original assignee: Bioxell SpA
Current assignee: Bioxell SpA
Priority date: 2006-09-22
Filing date: 2007-09-21
Publication date: 2009-09-23
Also published as: GB0618700D0; BRPI0717036A2

Abstract

There is provided a method of prevention of adhesions, e. g. surgical adhesions, which comprises using a vitamin D compound.

Description

Vitamin D compounds is used for the purposes of Film with Preventing Adhesion

Invention field

The chemical compound that the present invention relates to new purposes and method and be used for described purposes particularly is the purposes of vitamin D compounds class in Film with Preventing Adhesion.

Background of invention

The important clinical problem relevant with other tissue repair with peritoneum is the formation of adhesion.When closely adjacent surface sustains damage, for example because the damage that operation wound, mechanical injuries, ischemia injury, inflammation, chemical damage, radiotherapy, infection or other foreign body reactions cause has formed adhesion.

The reason of the particular importance of adhesion is because surgical operation.The formation of adhesion and to form be ill major reason again in the operation venter posterior.Postoperative intestinal adhesion can cause intestinal obstruction.The adhesion that was caused by former surgical operation can increase operation number of times and the complication that increases in the operation, comprises intestinal, bladder, ureteral damage and hemorrhage.

The adhesion of pelvis can cause sterile and pain.Thereby adhesion can stop the recovery of oocyte to cause sterile by causing that the fallopian tube mechanicalness is stopped up.

Some surgical operation tends to special related with the formation existence of adhesion, for example cholecystectomy, appendectomy, colonic operation and operation on pelvis.

Adhesion is particularly relevant with peritoneum, but they also may be relevant with the tissue of thoracic cavity, heart, spinal column, joint, eye and nose etc.

When adhesion was relevant with inflammation or course of infection, they may be relevant with for example peritonitis, pericarditis, pleuritis, cholecystitis and pelvic inflammatory disease.

Adhesion incidence rate behind the surgical operation is 55-94%, and is higher in the gynecologic surgery incidence rate.These percentage ratios may be coarse, because can not diagnose adhesion by imaging modality, and lack can be to its blood test of diagnosing.At present, confirm that the unique method that postoperative intestinal adhesion forms is to observe when another time performed the operation.

The incidence rate of postoperative intestinal adhesion increases along with the allogenic material of introducing body, for example from the Pulvis Talci of surgical glove.

The development of postoperative intestinal adhesion was considered to betide in surgical operation 3-5 subsequently days.Therefore, regulating agglutination during this period drops to minimum (with being hopeful Film with Preventing Adhesion) rather crucial for the development with postoperative intestinal adhesion.

Beginning that adhesion forms is the formation that starts from fibrin matrix, and it takes place under the situation that fibrinolytic effect existence suppresses in coagulation process usually.The surgical injury of tissue reduces or has eliminated blood flow, thereby produces ischemia, and it causes the part of fibrin matrix to retain.This substrate is little by little replaced by the blood vessel granulation tissue.Final adhesion maturation forms the fibrous ribbon that usually comprises the calcification tubercle.Adhesion is covered by a cortex usually, and comprises blood vessel and connective fiber.In the pelvis adhesion, found nervous tissue, comprised those adhesions with pelycalgia medical history.

The current Perfected process that does not have Film with Preventing Adhesion to form or form again.From surgical technic, recommend to adopt gentle organized processing, accurate hemostasis, a large amount of lavation, prevention infection and avoid foreign body reaction (for example, owing to use due to the glove that have powder).Medicine (for example steroid class and cox 2 inhibitor) and the medicine (for example tissue plasminogen activator) of fibrin degradation or the medicine (for example heparin) that prevention is solidified of prevention of inflammation have been assessed.Present commercially available method comprises physical barriers, and it plays a role by the tissue of separating damaged effectively.This separation can be by using solid mechanical barrier (thin film and gel, for example Interceed or Seprafilm) or using liquid to realize by the floating effect of aquation (icodextrin).But most barrier approach may be unaccommodated, because be difficult to operation, be not suitable for the operation (for example they may be not suitable for laparoscopic surgery) of some type, and it may increase the seepage of anastomosis, even may lose efficacy in the presence of blood.Because icodextrin solution support bacteria growth, when the risk of bacterial infection, their application is incompatible, so this is its main shortcoming.

US2005/0281883A (Daniloff) discloses crosslinked in position compositions, and it is said and can be used for reducing adhesion.According to its content, compositions can with the combination of the fibrosis medicine of certain limit, described fibrosis medicated bag is drawn together inosine monophosphate dehydrogenase inhibitor, 1-α for example, 25-dihydroxy vitamin d3 or its analog or derivant.

WO2006/094064 (Avocet Polymer Technologies company) relates to the outward appearance of improving closure of wound and/or the method and composition that reduces its size, and it comprises uses vitamin D or active vitamin D-derivatives.

US5,194,248 (Boston Universities) relate to the method that novel vitamin D analogues is provided to skin, and it is by using the medicine that can be converted into vitamin D Precursors by low-energy ultraviolet light.This method it is said and can be used for wound healing and suppress cicatrization.

In general, the method for existing treatment adhesion has only obtained limited success.Therefore being starved of more selective and specific method comes Film with Preventing Adhesion, and described method should not have well-known shortcoming in the present method.

Summary of the invention

In order to relax and to alleviate above-mentioned shortcoming, the present invention has developed the postoperative adhesion of the new method of Film with Preventing Adhesion, particularly prevention of surgical.This method is based on the application of calcitriol and analog (it is referred to as " vitamin D compounds " in this article) thereof.

(Mellanby, E. (1921) Spec.Rep.Ser.Med.Res.Council (GB) SRS 61:4) it has been recognized that its importance in the higher mammal biosystem since Mellanby finds vitamin D (cholecalciferol) in nineteen twenty.Vitamin D is formally classified as " vitamin " in the period of 1920-1930 just, its be normal development of skeleton and keep calcium and the homeostasis of phosphorus necessary.

About vitamin D ₃Metabolic research starts from blood plasma metabolite 25-hydroxy-vitamin D ₃[25 (OH) D ₃] (Blunt, people such as J.W.. (1968) Biochemistry 6:3317-3322) and hormonal activity form 1-α, 25 (OH) ₂D ₃(Myrtle, people such as J.F.. (1970) J.Biol.Chem.245:1190-1196; Norman, people such as A.W.. (1971) Science 173:51-54; Lawson, people such as D.E.M.. (1971) Nature 230:228-230; Holick, M.F. (1971) Proc.Natl.Acad.Sci.USA 68:803-804) discovery and chemical descriptor.The statement of the notion of vitamin D hormonal system depends on kidney is being produced 1-α, 25 (OH) with careful control methods ₂D ₃In understanding (Fraser, D.R. and Kodicek, E (1970) the Nature 288:764-766 of pivotal role; Wong, people such as R.G.. (1972) J.Clin.Invest.51:1287-1291) and intestinal in 1-α, 25 (OH) ₂D ₃Nuclear receptor (VD ₃Discovery R) (Haussler, people such as M.R.. (1969) Exp.Cell Res.58:234-242; Tsai, H.C. and Norman, A.W. (1972) J.Biol.Chem.248:5967-5975).

The operation of vitamin D hormonal system depends on following factors: the first, and cytochrome P 450 enzymes is at liver (Bergman, T. and Postlind, H. (1991) Biochem.J.276:427-432; Ohyama, Y and Okuda, K. (1991) J.Biol.Chem.266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J.Biol.Chem.249:7529-7535; Gray, R.W. and Ghazarian, J.G. (1989) Biochem.J.259:561-568) in and the existence in multiple its hetero-organization, to realize vitamin D ₃To bioactive metabolites 1-α for example, 25 (OH) ₂D ₃And 24R, 25 (OH) ₂D ₃Conversion; Second, the existence of blood plasma vitamin D binding protein (DBP), with realize these hydrophobic molecule to the selective transport of the various structural constituents of vitamin D hormonal system and send (Van Baelen, people such as H.. (1988) Ann NY Acad.Sci.538:60-68; Cooke, N.E. and Haddad, J.G. (1989) Endocr.Rev.10:294-307; Bikle, people such as D.D.. (1986) J.Clin.Endocrinol.Metab.63:954-959); The 3rd, the existence of stereo selectivity receptor in multiple target tissue, described receptor and agonist 1-α, 25 (OH) ₂D ₃Interaction is to produce the specific biological response (Pike, J.W. (1991) Annu.Rev.Nutr.11:189-216) to necessity of this open loop steroid hormone.Up to now, evidence suggests 1-α, 25 (OH) ₂D ₃Nuclear receptor (VD ₃R) be present in the tissue and cancerous cell line more than 30 kinds (Reichel, H. and Norman, A.W. (1989) Annu.Rev.Med.40:71-78), comprise normal eye (people .Curr Eye Res.1995 such as Johnson JA February; 14 (2): 101-8).

Vitamin D ₃And the hormonal activity form is the regulator of well-known calcium and phosphorus homeostasis.Known these chemical compounds stimulate at least a following effects: the transfer of the intestinal absorption of calcium and phosphorus, bone mineral nitrogen and the stop of calcium in kidney.In addition, find that in the tissue of kind more than 30 specific vitamin D receptor exists, this causes vitamin D ₃Be confirmed as except that the multipotency regulator its classics effect in calcium/bone stable state.Can be with vitamin D ₃The enzyme that is oxidized to its activity form for example 25-OHD-1-α-hydroxylase and specific receptor has been pointed out 1-α, 25 (OH) in the multiple existence of organizing in for example bone, keratinocyte, Placenta Hominis and the immunocyte of uniting ₂D ₃Paracrine action.And, have been found that vitamin D ₃Hormone and active metabolite can regulate the cell proliferation of normal cell and malignant cell and differentiation (Reichel, people such as H.. (1989) Ann.Rev.Med.40:71-78).

Because vitamin D ₃And the activity of metabolite, a lot of concerns have concentrated on the exploitation of the synthetic analogues of these chemical compounds.A lot of these analog involve the structural modification of A ring, B ring, C/D ring, and mainly be side chain structural modification (Bouillon, people such as R.. (1995) Endocrine Reviews16 (2): 201-204).Although the vitamin D that great majority are developed so far ₃Analog involves the structural modification of side chain, but a small amount of research reported A ring diastereomer biological nature (Norman, people such as A.W.. (1993) J.Biol.Chem.268 (27): 20022-20030).In addition, after deliberation the biological esterification effect of steroid class (Hochberg, R.B., (1998) Endocr Rev.19 (3): 331-348), and vitamin D ₃Ester be known (WO 97/11053).

And, although for the exploitation synthetic analogues has been paid a large amount of effort, but the clinical practice of vitamin D and analog thereof is still limited by undesirable side effect, and described side effect is these chemical compounds to be used for known indications/application back of vitamin D compounds caused being applied to individuality.

The activated form of vitamin D, vitamin D ₃Be described to effective regulator that cell is grown and broken up with some its analog.Had been found that vitamin D in the past ₃And analog (analog V) suppresses the BPH cell proliferation, and opposing is to the effective somatomedin of the BPH cell mitogenic activity of keratinocyte growth factor (KGF) and insulin like growth factor (IGF1) for example.And this analog induces bcl-2 protein expression, intracellular calcium to transfer and apoptosis in the BPH cell that stimulates with KGF-that stimulates.

Described in the embodiment of this paper, the inventor have been found that the analog (" compounds X " among the embodiment and " chemical compound Y ") of vitamin D compounds such as calcitriol and calcitriol can be in the model of animal model such as mice and rabbit Film with Preventing Adhesion.

Under the situation of bound by theory not, think that vitamin D compounds brings into play its useful effect by regulating the fibrinolysis approach and having antiinflammatory action.Being proved in embodiment, this useful effect can realize under the situation that wound healing is not had adverse effect.In theory, in case form fibrous adhesion, just can't expect that the fibrosis medicine can effectively and not influence agglutination in eliminating adhesion.But, have been found that vitamin D compounds is effective.And as if what be different from some art methods is that it is to by infecting mortality rate due to strengthening without any adverse influence.

Therefore, the invention provides the purposes of vitamin D compounds in Film with Preventing Adhesion on the one hand.The method of preventing individual adhesion by the vitamin D compounds of using effective dose also is provided.The purposes of vitamin D compounds in the medicine of preparation Film with Preventing Adhesion also is provided.The vitamin D compounds that is used for Film with Preventing Adhesion also is provided.Also provide medicine box, thereby it comprises vitamin D compounds and relevant description from described chemical compound Film with Preventing Adhesion in described patient to the patient who needs Film with Preventing Adhesion that use.

On the one hand, the invention provides the method for using the vitamin D compounds Film with Preventing Adhesion.

On the other hand, the invention provides the method for Film with Preventing Adhesion in individuality, this method comprises vitamin D compounds from effective dose to its individuality of needs that use, so as in this individuality Film with Preventing Adhesion.

In one embodiment, the invention provides aforesaid method, it also comprises differentiates the individuality that needs Film with Preventing Adhesion.In another embodiment, the invention provides aforesaid method, it also comprises the step that obtains vitamin D compounds.In an embodiment of method as herein described, individuality is a mammal.In another embodiment, individuality is the people.

In another embodiment, the invention provides method as described herein, wherein vitamin D compounds is configured to pharmaceutical composition with acceptable diluents or carrier.

On the other hand, the invention provides the purposes of vitamin D compounds in the medicine of preparation Film with Preventing Adhesion.

On the other hand, the invention provides the pharmaceutical preparation that comprises vitamin D compounds and pharmaceutically suitable carrier, it is used for Film with Preventing Adhesion.

On the other hand, the invention provides the pharmaceutical preparation that comprises vitamin D compounds and pharmaceutically suitable carrier, it is packed with the description that is used for Film with Preventing Adhesion.

On the other hand, the invention provides the vitamin D compounds that is used for Film with Preventing Adhesion.

The invention provides the medicine box that comprises vitamin D compounds and description, thereby described description is about use described chemical compound Film with Preventing Adhesion in described patient to the patient who needs Film with Preventing Adhesion.

In one embodiment, the invention provides purposes, method, preparation, chemical compound or medicine box, wherein vitamin D compounds in pharmaceutical preparation that separate or combination with second medicine that prevents and/or treats adhesion separately, successively or use simultaneously.In another embodiment, the invention provides purposes, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds is calcitriol, as hereinafter defined compounds X or chemical compound Y.

The accompanying drawing summary

Fig. 1 has shown the comparison of adhesion scoring after administered compound X or solvent.

Fig. 2 has shown the comparison of adhesion scoring after administered compound Y or solvent.

Fig. 3 has shown (last figure) adhesion scoring after administered compound X, Y, calcitriol or solvent and the comparison of (figure below) corresponding adhesion length.

Fig. 4 has shown the serum calcium level of laboratory animal after administered compound X, Y, calcitriol or solvent.

Fig. 5 has shown the serum calcium level of laboratory animal after the chemical compound Y that uses various dose: last figure has shown the result after intraperitoneal administration (single dose), and figure below has shown in intraperitoneal administration (single dose) and with the result of MTD (3ug/kg) oral administration after 3 days.

Fig. 6 has shown in the comparison of using leuprorelin acetate (positive control) or solvent posterior synechiae scoring.

Fig. 7 has shown the interaction in vitro of chemical compound Y to the fibrinolysis approach, and the dissolving of the fibrin clot of the supernatant of being cultivated by l cell 3T3.L1 condition proves.

Fig. 8 has shown the interaction in vitro of chemical compound Y to the fibrinolysis approach, is proved by the tPA/PAI ratio among people's the mesothelial cell.

Fig. 9 has shown that single administration chemical compound Y is to the influence of serum calcium level in the mouse peritoneum.

Figure 10 has shown the dosage-response effect research (CPSS) of chemical compound Y in mice surgical operation posterior synechiae model.

Figure 11 has shown the dosage-response effect research (DUH) of chemical compound Y in rabbit surgical operation posterior synechiae model.

Figure 12 has shown the influence to serum calcium level to DUH rabbit intraperitoneal single administration chemical compound Y.

Figure 13 has shown the effect of chemical compound Y in the mouse model of organization healing.

Figure 14 has shown the influence of chemical compound Y to mice VEGF and TGF-B level.

Figure 15 has shown the effect of chemical compound Y in the mouse death rate model due to strengthening owing to infection.

Figure 16 has shown the effectiveness that chemical compound Y compares with icodextrin in the DUH rabbit model.

Figure 17 has shown the effectiveness that chemical compound Y compares with lazaroids in the DUH rabbit model.

Detailed Description Of The Invention

1. definition

Before further explanation the present invention, in order more easily to understand the present invention, at first define and concentrated some term herein for the purpose of convenient.

" adhesion " refers to that unwanted fiber connects between the tissue (the particularly connection of persistent fibre substrate formation), such as the tissue of peritonaeum, thoracic cavity, heart, backbone, joint, eye, nose etc. This class connects the situation that may derive from multiple pathogenic property, for example surgery operation or potential morbid state. The situation that especially, can form adhesion comprises gynecological operation and caesarean birth. Should be appreciated that many potential chronic diseases can cause the formation of adhesion sometimes, for example inflammatory bowel is sick, Crow grace is sick, uterus endometrium ectopia and ulcer colitis, and these potential chronic diseases itself are not comprised in the term " adhesion ". In an embodiment, use the individuality that vitamin D compounds comes preventing adhesions and do not suffer from the uterus endometrium ectopia. In second embodiment, use individuality that vitamin D compounds comes preventing adhesions and do not suffer from that inflammatory bowel disease, Crow grace are sick, uterus endometrium ectopia or ulcer colitis.

When using in the prevention of the relevant adhesion of this paper, " prevention " refers to reduce the size/seriousness of the adhesion of the quantity that forms adhesion and/or formation. Because the formation of adhesion relates to molecular components and the process in a plurality of stages of process of certain limit, should be understood that, " prevention " be included in Adhesion formation begin before and in office what in vitamin D compounds stage of be used for reversing the Adhesion formation process use vitamin D compounds. " prevention " do not expand to the treatment of the adhesion of former existence or therein the vitamin D compounds Adhesion formation that can not reverse the Adhesion formation process use the vitamin D compound in the stage.

" peritoneal adhesion " refers to the adhesion of peritonaeum, and for example adhesion of abdominal cavity and pelvis is normally by surgery operation, ischemia injury, inflammation, bacillary and chemical peritonitis, radiotherapy or foreign matter reaction cause.

" postoperative intestinal adhesion " refers in the adhesion of formation between the tissue after the surgery operation, described operation includes, but is not limited to traditional operation and celioscopy, for example cholecystectomy, appendectomy, colonic operation, openheart surgery, lung operation and pelvic cavity operation.

It will be appreciated by those skilled in the art that described vitamin D compounds can be used for human medical science and veterinary science. Therefore, term of the present invention " individuality " and " patient " are used interchangeably, and have comprised for example people of mammal. Preferred described vitamin D compounds is used for the adhesion of prevention human patients.

Term administering " or " administration " comprise to individuality and introduce vitamin D compounds to bring into play the approach of their expectation functions. The example of the route of administration that can use comprise injection (in subcutaneous, the vein, in the parenteral, peritonaeum) or oral, suction, rectum or transdermal administration or via for example bladder instil or peritonaeum in instil. Yes gives with the form that is suitable for every kind of route of administration for the medicine preparation. For example, by injecting, fail notes, suction, lotion, ointment agent, suppository etc., using these preparations with the form of tablet or capsule. Preferred oral is used or directly peritonaeum is used (that is, approach in the peritonaeum). Injection can be to inject or can be continuous infusion. According to the approach of using, vitamin D compounds can or place selected material with selected material dressing, avoids having on its ability of bringing into play expectation function the natural condition of harmful impact to protect it. Vitamin D compounds can be used separately or the two is co-administered with another kind material (for example anti-inflammatory agent such as cortical steroid, and fibrinolytic medicine such as tissue plasmin activator) that is used for prevention and/or treatment adhesion or with pharmaceutically useful carrier or this. Vitamin D compounds can be before using another kind material, use simultaneously or after using this material with this material. In addition, vitamin D compounds also can be used with precursor forms, and it is converted into its active metabolite or more highly active metabolin is arranged in body.

Term " effectively amount " is included in the amount that effectively reaches required result in necessary dosage and the time section, namely is enough to the amount of preventing adhesions. Effective amount of vitamin D compounds can be different because of many factors, the age of the background that described factor is for example fallen ill (that is, potential morbid state or related particular procedure operation), individuality and body weight and vitamin D compounds cause the ability of required response in individuality. Can regulate dosage regimen, so that best prophylactic effect to be provided. The preventative beneficial effect that effective amount also is vitamin D compounds is better than the amount of any toxicity and harmful effect (for example side effect).

The prevention of vitamin D compounds is effectively measured (namely, effective dose) can be about 0.001 to 30 μ g/kg body weight every day, preferred about 0.01 to 25 μ g/kg body weight, 0.1 to 20 μ g/kg body weight more preferably from about, even more preferably from about 1 to 10 μ g/kg, 2 to 9 μ g/kg, 3 to 8 μ g/kg, 4 to 7 μ g/kg or 5 to 6 μ g/kg body weight. Higher concentration, for example maximum 600 μ g/kg also can be tolerated. Those skilled in the art will recognize that, some factor may affect the required dosage of the individual adhesion of effective prevention, includes but not limited to the seriousness of disease or illness, former treatment, the general health status of individuality and/or the other diseases of age and existence. In addition, the dosage of using also will depend on employed specified vitamin D compound, and effective amount of every kind of compound can be determined by the method for tiring known in the art. In addition, the vitamin D compounds that adopts prevention effectively to measure prevents individual Adhesion formation can comprise single-dose, perhaps preferably can comprise a series of administrations. In an example, use vitamin D compounds to individuality, dosage is about 0.1 to 20 μ g/kg body weight, once a day, continues for 1 or 2 weeks, for example uses in the short time before elective surgery begins or after the operation end.

Also can consider " opening-close (on-off) " or intermittent dosage regimen. What will be appreciated that is that the effective dose of the vitamin D compounds that preventing adhesions is used can increase or reduce along with the process in specific administration cycle.

Term " alkyl " expression radical of saturated aliphatic group comprises the cycloalkyl of straight chained alkyl, side chain alkyl, cycloalkyl (alicyclic group), alkyl replacement and the alkyl that cycloalkyl replaces. The term alkyl further comprises such alkyl, they can comprise further that oxygen, nitrogen, sulphur or phosphorus atoms are to replace the one or more carbon in the hydrocarbon skeleton with choosing wantonly, for example oxygen, nitrogen, sulphur or phosphorus atoms (for example, alkyl does not comprise above-mentioned atom in one embodiment). In preferred embodiments, the straight or branched alkyl in its skeleton, have carbon atom below 30 or 30 (for example for straight chain, C₁-C ₃₀, for side chain, C₃-C ₃₀), preferred below 26 or 26, more preferably below 20 or 20, especially below 6 or 6. Equally, preferred cycloalkyl has 3-10 carbon atom in its ring structure, more preferably have 3,4,5,6 or 7 carbon in ring structure.

In addition, employed term alkyl is intended to comprise " alkyl that does not replace " and " alkyl of replacement " in whole specification and the claim book, and the latter represents to have substituting group to replace the moieties of the hydrogen on the one or more carbon in the hydrocarbon skeleton. This class substituting group can comprise for example part of halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxycarbonyl oxygen base, carboxylate, alkyl-carbonyl, alkoxy carbonyl, amino carbonyl, alkylthio group carbonyl, alkoxyl, phosphoric acid ester, phosphine acyl group (phosphonato), inferior phosphine acyl group (phosphinato), cyano group, amino (comprising alkyl amino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprising alkyl-carbonyl-amino, aryl-amino-carbonyl, carbamyl and urea groups), amidino groups, imino group, sulfydryl, alkylthio group, arylthio, carbothioic acid ester, sulfuric ester, sulfonic group (sulfonato), sulfamoyl, sulfonamido, nitro, three methyl fluorides, cyano group, azido, heterocycle base, alkyl aryl or aromatics or assorted aromatics. It will be appreciated by those skilled in the art that if suitably, can be substituted in the part of hydrocarbon chain substitution itself. Cycloalkyl can further be replaced by example substituting group described above.

The alkyl (for example benzyl (benzyl)) that " alkyl aryl " part is replaced by aryl. Alkyl (the comprising cycloalkyl) group that does not replace, or the alkyl that is replaced by halogen, particularly fluorine is preferred with respect to other substituted groups generally. Term " alkyl " be also included within be similar in length and the possible replacement abovementioned alkyl, but contain respectively the undersaturated aliphatic group of at least one two key or three key.

Unless the carbon number is had regulation in addition, otherwise " low alkyl group " used herein represents as defined above alkyl, but in its skeleton structure, have 1 to 10 carbon, more preferably 1 to 6,1 to 4 carbon atom most preferably, it can be straight or branched. The example of low alkyl group comprises methyl, ethyl, propyl group (n-pro-pyl and isopropyl), butyl (tert-butyl group, normal-butyl and Zhong Dingji), amyl group, hexyl, heptyl, octyl group etc. In preferred embodiments, term " low alkyl group " is included in the straight chained alkyl that has 4 or 4 following carbon atoms in its skeleton, for example C₁-C ₄Alkyl.

Therefore, the concrete example of alkyl comprises C_1-6Alkyl or C_1-4Alkyl (for example methyl or ethyl). The concrete example of hydroxy alkyl comprises C_1-6Hydroxy alkyl or C_1-4Hydroxy alkyl (for example methylol).

Term " alkoxyalkyl ", " polyamino alkyl " and " thio alkoxy alkyl " expression alkyl as mentioned above, they comprise that further oxygen, nitrogen or sulphur atom replace the one or more carbon in the hydrocarbon skeleton, for example oxygen, nitrogen or sulphur atom.

Term used herein " aryl " expression aromatic yl group, comprise 5-and 6-unit mono-cyclic aromatic group, it can comprise 0 to 4 hetero atom, such as benzene, pyrroles, furans, thiophene, imidazoles, benzene and Evil azoles, benzothiazole, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc. Aryl also comprises many ring fused aromatic groups, such as naphthyl, quinoline base, indyl etc.

In ring structure, have heteroatomic those aryl and also can be called " aryl-heterocyclic ", " assorted aryl " or " heteroaromatic group ". Aromatic ring can be replaced by above-mentioned substituting group on one or more ring positions, for example halogen, hydroxyl, alkoxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxycarbonyl oxygen base, carboxylate, alkyl-carbonyl, alkoxy carbonyl, amino carbonyl, alkylthio group carbonyl, phosphoric acid ester, phosphine acyl group, inferior phosphine acyl group, cyano group, amino (comprising alkyl amino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprising alkyl-carbonyl-amino, aryl-amino-carbonyl, carbamyl and urea groups), amidino groups, imino group, sulfydryl, alkylthio group, arylthio, carbothioic acid ester, sulfuric ester, sulfonic group, sulfamoyl, sulfonamido, nitro, three methyl fluorides, cyano group, azido, heterocycle base, alkyl aryl or aromatics or heteroaromatic moiety. Aryl also can be not that the fat ring family of armaticity or heterocyclic fused or bridging are to form many rings (for example naphthanes).

Term " alkene base " and " alkynes base " expression length and possible replacement be similar to abovementioned alkyl, but contain respectively the undersaturated aliphatic group of at least one two key or three key. For example, cyano group and propargyl are contained in the present invention.

Term " chirality " expression have the mirror image companion can not sumproperties molecule, and the stackable mirror image companion's in them of term " achirality " expression molecule.

Term " diastereomer " expression has the stereoisomer of two or more asymmetric centers, and their molecule is not a mirror image each other.

Two kinds of stereoisomers of term " enantiomer " expression chemical compound, they are each other can not synergetic mirror image.The molar mixture that waits of two kinds of enantiomer is called as " racemic mixture " or " racemate ".

Term used herein " halogen " expression-F ,-Cl ,-Br or-I; Term " sulfydryl " or " mercaptan " expression-SH; Term " hydroxyl " expression-OH.

Term " haloalkyl " be intended to comprise by the halogen list-, two-or many-alkyl defined above of replacing, for example C _1-6Haloalkyl or C _1-4Haloalkyl, for example methyl fluoride and trifluoromethyl.

Atoms of elements beyond term used herein " hetero atom " any de-carbon of expression or the hydrogen.Preferred hetero atom is nitrogen, oxygen, sulfur and phosphorus.

The group (for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical) of the two or more cyclic rings of term " multi-ring base " or " multi-ring group " expression, shared two or more carbon of the ring of two adjacency wherein, for example these rings are " fused rings ".The ring that connects by non-conterminous atom is called as " bridging " ring.Polycyclic each ring can be replaced by above-mentioned substituent group, for example halogen; hydroxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxycarbonyl oxygen base; carboxylate; alkyl-carbonyl; alkoxy carbonyl; amino carbonyl; the alkylthio group carbonyl; alkoxyl; phosphate ester; phosphono; inferior phosphono; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamyl and urea groups); amidino groups; imino group; sulfydryl; alkylthio group; arylthio; carbothioic acid ester; sulfuric ester; sulfonic group; sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkyl; alkylaryl or aromatics or heteroaromatic moiety.

Term " isomer " or " stereoisomer " expression have identical chemical composition, but aspect the spatial arrangements of atom or group different chemical compounds.

Term " isolating " or " pure basically " are used interchangeably in this article, the vitamin D of expression non-natural existence ₃Chemical compound.These chemical compounds can be substantially free of cellular material or culture medium when natural generation, perhaps can be substantially free of precursor or other chemical substances when chemosynthesis.In one embodiment of the invention, by w/w, isolating vitamin D compounds is at least 75% purity, at least 85% purity particularly, especially at least 95% purity, at least 99% purity preferably, described purity with reference to and the natural relevant chemical compound of vitamin D compounds, or in the chemosynthesis process chemical compound relevant with its chemistry.

In certain preferred aspects, term " separation " or " pure basically " also represent not have basically the prepared product of the chipal compounds of one of enantiomer; Be the enantiomer enrichment or the non-racemic prepared product of molecule.

Similarly, term " isolating epimer " or " isolating diastereomer " expression is substantially free of the prepared product of the chipal compounds of other stereochemical forms.For example, isolating or pure basically vitamin D ₃Chemical compound comprises having the vitamin D that is connected in the substituent stereoisomer enrichment on 3 chiral carbon of A-ring with α-configuration ₃Synthetic or natural prepared product, thereby do not have other to have the isomer of beta configuration basically.Unless otherwise prescribed, otherwise the weight ratio that wherein α and beta form represented in this class term greater than 1: 1 vitamin D ₃Composition.For example, the prepared product of isolating epimer is represented to have for β-stereoisomer greater than 50 weight %, the more preferably at least 75 weight % even the more preferably prepared product of α-epimer of at least 85 weight %.Certainly, enrichment can be far longer than 85%, and " being essentially epimer-enrichment " prepared product is provided, and promptly has for β-stereoisomer greater than 90% even more preferably greater than the compound thing of α-epimer of 95%.Term " is substantially free of β-stereoisomer " and is interpreted as having similar purity range.

Term used herein " vitamin D compounds " comprise any can Film with Preventing Adhesion be the chemical compound of novel vitamin D analogues.Generally speaking, be regarded as within the scope of the invention for vitamin D receptor part (VDR part) and chemical compound that can Film with Preventing Adhesion.Vitamin D compounds is the agonist of vitamin D receptor preferably.Therefore, vitamin D compounds is intended to comprise open loop steroid class.The example that is applicable to the concrete vitamin D compounds of the inventive method further describes in this article.Vitamin D compounds comprises vitamin D ₂Chemical compound, vitamin D ₃Chemical compound, its isomer or its derivant/analog.Preferred vitamin D compounds is a vitamin D ₃Chemical compound, they are parts (being more preferably agonist) of vitamin D receptor.Preferably, vitamin D compounds (vitamin D for example ₃Chemical compound) be than native ligand (be vitamin D, vitamin D for example ₃) more effective vitamin D receptor agonist.Vitamin D ₁Chemical compound, vitamin D ₂Chemical compound and vitamin D ₃Chemical compound comprises vitamin D respectively ₁, D ₂, D ₃With its analog.In certain embodiments, vitamin D compounds can be the steroid class, for example open loop steroid class, for example cholecalciferol, calcifediol or calcitriol.The limiting examples of some preferred vitamin D compounds of the present invention is included in U.S. Pat 6,492,353 and the International Application No. WO 2005/030222 announced in describe those.

As used herein, term " acquisition " comprise purchase, synthetic, separate or otherwise obtain one or more and be used to implement vitamin D compounds of the present invention.

Term " open loop steroid class " is art-recognized, comprises the chemical compound of one of the Pentamethylene. of cyclopentanoperhydro-phenanthrene structure wherein and the ring of many hydrogen phenanthrene fracture.For example, 1-α, 25 (OH) ₂D ₃And analog is the open loop steroid class that hormonal activity is arranged.At vitamin D ₃Situation under, the 9-10 carbon-to-carbon rupture of B-ring generates open loop-B-steroid class.Vitamin D ₃Formal IUPAC name be called 9,10-open loop gallbladder steroid-5,7,10 (19)-triolefins-3B-alcohol.For convenience, the 1-α that this paper sets forth, 25 (OH) ₂D ₃The isomer of 6-s-transoid conformation, all carbon atoms all are numbered with the steroidal representation of standard.

In the listed structural formula of this paper, the various substituent groups on the ring A were set forth with being connected with one of following these representations of steroid nucleus: dotted line (----) expression substituent group is β-orientation (that is, more than plane of a loop), the wedge shape solid line (

) expression substituent group be α-orientation (that is, below planes of molecules), perhaps wave ( ) expression substituent group can more than the plane of a loop or below.About ring A, should be understood that, conventional and the general chemical field of spatial chemistry in the vitamin D field is opposite, substituent group in general chemical field on the dotted line representative ring A be α-orientation (promptly, below planes of molecules), substituent group on the wedge shape solid line representative ring A is β-orientation (that is, more than a plane of a loop).

In addition, the stereochemical expression of crossing over carbon-to-carbon double bond is also opposite with general chemical field, and " Z " expression often is called as the conformation of " cis " (homonymy) in general chemical field, and " E " expression often is called as the conformation of " trans " (heteropleural).In any case two kinds of configurations: cis/trans and/or Z/E are suitable for chemical compound of the present invention.

Just as illustrated, hormone 1-α, 25 (OH) ₂D ₃A ring contain two asymmetric centers at

carbon

1 and 3, each asymmetric center all contains the hydroxyl that configuration is fully described, i.e. 1-α-and 3-beta-hydroxy.In other words, the

carbon

1 and 3 of A ring is " chiral carbon " or " carbon center ".

About the name of chiral centre, term " d " and " l " configuration define with IUPACRecommendations.As for the use of term, diastereomer, racemate, epimer and enantiomer will be described the spatial chemistry of prepared product with their normal implication.

And, in patent document, any one under the A of vitamin D compounds ring often is depicted as in general structural formula in the array structure:

X wherein ₁And X ₂Be defined as H or=CH ₂Perhaps

X wherein ₁And X ₂Be defined as H ₂Or CH ₂

As if although without any set routine, obviously those of ordinary skills understand formula (A) or (B) the following A of representative encircle X for example wherein ₁Be=CH ₂And X ₂Be defined as H ₂:

For purpose of the present invention, in all general structures, will use formula (B).

In one embodiment of the invention, vitamin D compounds is the chemical compound of formula (I):

Wherein:

X is hydroxyl or fluorine;

Y is H ₂Or CH ₂

Z ₁And Z ₂Be the substituent group shown in H or the formula (II), condition is Z ₁And Z ₂Be different (preferred Z ₁And Z ₂Expression (II) not all):

Wherein:

Z ₃Represent above-mentioned formula (I);

A is singly-bound or two key;

R ₁, R ₂And Z ₄Be the saturated or undersaturated carbochain shown in hydrogen, alkyl or the formula (III) independently of one another, condition is R ₁, R ₂And Z ₄Have at least one to be the saturated or undersaturated carbochain shown in the formula (III), and condition is R ₁, R ₂And Z ₄Not all be the saturated or undersaturated carbochain shown in the formula (III):

Wherein:

Z ₅Represent above-mentioned formula (II);

A ₂Be singly-bound, two key or three key;

A ₃Be singly-bound or two key;

R ₃And R ₄Be hydrogen, alkyl, haloalkyl, hydroxy alkyl independently of one another; And R ₅Be H ₂Or oxygen.R ₅Also can represent hydrogen or can not exist.

Therefore, in above formula (III) structure (with corresponding structure hereinafter), work as A ₂When representing three key, R ₅Do not exist.Work as A ₂During the two key of representative, R ₅Represent hydrogen.Work as A ₂When representing singly-bound, R ₅Represent carbonyl or two hydrogen atoms.

In another embodiment of the present invention, vitamin D compounds is the chemical compound of formula (IV):

Wherein:

X ₁And X ₂Be H ₂Or CH ₂, X wherein ₁And X ₂Not CH simultaneously ₂

A is singly-bound or two key;

A ₂Be singly-bound, two key or three key;

A ₃Be singly-bound or two key;

R ₁And R ₂Be hydrogen, C ₁-C ₄Alkyl or 4-hydroxy-4-methyl amyl group, wherein R ₁And R ₂Not all be hydrogen;

R ₅Be H ₂Or oxygen, R ₅Also can represent hydrogen or can not exist;

R ₃Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, for example fluoro-alkyl, for example methyl fluoride and trifluoromethyl;

R ₄Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, for example fluoro-alkyl, for example methyl fluoride and trifluoromethyl.

In another embodiment of the present invention, vitamin D compounds is the chemical compound of formula V:

Wherein:

A is singly-bound or two key;

A ₂Be singly-bound, two key or three key;

A ₃Be singly-bound or two key;

R ₁And R ₂Be hydrogen, C ₁-C ₄Alkyl, wherein R ₁And R ₂Not all be hydrogen;

R ₅Be H ₂Or oxygen, R ₅Also can represent hydrogen or can not exist;

The example of above formula V structure is 1,25-dihydroxy-16-alkene-23-alkynes cholecalciferol.

In another embodiment, vitamin D compounds is formula (VI) " geminal (geminal) " chemical compound:

Wherein:

X ₁Be H ₂Or CH ₂

A ₂Be singly-bound, two key or three key;

R ₄Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, for example fluoro-alkyl, for example methyl fluoride and trifluoromethyl;

C ₂₀Configuration be R or S.

Because at C ₂₀Two alkyl chains of last existence, such chemical compound can be called as " geminal " or " together with " vitamin D ₃Chemical compound.

The geminal examples for compounds of formula (VI) is 1, and 25-dihydroxy-21-(3-hydroxy-3-methyl butyl)-19-falls-cholecalciferol (being also referred to as " chemical compound Y " in this article):

In WO 98/49138 and US 6,030,962, having described 1,25-dihydroxy-21-(3-hydroxy-3-methyl butyl)-19-falls-cholecalciferol synthetic, its content is incorporated herein by reference.It is synthetic to have described this in the following Example 2.

In another embodiment, vitamin D compounds is the chemical compound of formula (VII):

Wherein:

A is singly-bound or two key;

R ₁And R ₂Be hydrogen, alkyl (for example methyl) independently of one another;

R ₃And R ₄Be alkyl independently of one another;

X is hydroxyl or fluorine.

In another embodiment, vitamin D compounds is the chemical compound of formula (VIII):

Wherein:

R ₁And R ₂Be hydrogen or alkyl, for example methyl independently of one another;

R ₃Be alkyl, methyl for example;

R ₄Be alkyl, methyl for example; And

X is hydroxyl or fluorine.

In specific embodiment of the present invention, vitamin D compounds is selected from down group:

In other specific embodiments of the present invention, vitamin D compounds is selected from down group:

In the other specific embodiment of the present invention, vitamin D compounds is selected from down the geminal chemical compound of group:

On the other hand, the invention provides the geminal vitamin D of formula (IX) ₃Chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₁, R ₂, R ₃And R ₄Be C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Deuterium substituted alkyl, hydroxy alkyl or haloalkyl;

R ₅, R ₆And R ₇Be hydroxyl, OC (O) C independently of one another ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

C ₂₀Configuration be R or S;

X ₁Be H ₂Or CH ₂

As at least one R ₁And R ₂Be C ₁-C ₄Deuterium substituted alkyl and at least one R ₃And R ₄When being haloalkyl, perhaps as at least one R ₁And R ₂Be haloalkyl and at least one R ₃And R ₄Be C ₁-C ₄During the deuterium substituted alkyl, Z is a hydrogen; Perhaps Z be-OH ,=O ,-SH or-NH ₂

The multiple embodiments of this respect of the present invention comprises various I chemical compound, wherein: A ₁It is singly-bound; A ₂It is singly-bound; A ₂It is three key; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; R ₁, R ₂, R ₃And R ₄Be C independently of one another ₁-C ₄Deuterium substituted alkyl or haloalkyl; R ₅It is hydroxyl; R ₆And R ₇It is hydroxyl; R ₆And R ₇Be respectively OC (O) C ₁-C ₄Alkyl; X ₁Be H ₂X ₁Be CH ₂Z is a hydroxyl; Or Z is=O.

In certain embodiments, R ₅, R ₆And R ₇It is hydroxyl.In other embodiments, R ₆And R ₇It is respectively acetyl group oxygen base.

In other embodiments, as at least one R ₁And R ₂Be C ₁-C ₄Deuterium substituted alkyl and at least one R ₃And R ₄When being haloalkyl, perhaps as at least one R ₁And R ₂Be haloalkyl and at least one R ₃And R ₄Be C ₁-C ₄During the deuterium substituted alkyl, Z is a hydrogen; Work as X ₁Be CH ₂The time Z be-OH ,=O ,-SH or-NH ₂Work as X ₁Be H ₂And C ₂₀Configuration when being S Z be-OH ,=O ,-SH or-NH ₂, perhaps work as X ₁Be H ₂And C ₂₀Configuration when being R Z be=O ,-SH or-NH ₂In one embodiment, Z is-OH.

Other embodiments of this respect of the present invention comprise those chemical compounds, wherein: X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is-OH.In one embodiment, X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is=O.In one embodiment, X ₁Be H ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; C ₂₀Configuration be S; And Z is-OH.In another embodiment, X ₁Be H ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is=O.In these embodiments, R ₁, R ₂, R ₃And R ₄Each methyl naturally advantageously.

In certain embodiments, haloalkyl is a fluoro-alkyl.Advantageously, fluoro-alkyl is fluoro methyl or trifluoromethyl.

Other embodiments of this respect of the present invention comprise such chemical compound, wherein: X ₁Be H ₂A ₂It is three key; R ₁And R ₂Each is C naturally ₁-C ₄The deuterium substituted alkyl; R ₃And R ₄Each is haloalkyl naturally; And Z is a hydrogen.In other embodiments, X ₁Be CH ₂A ₂It is three key; R ₁And R ₂Each is C naturally ₁-C ₄The deuterium substituted alkyl; R ₃And R ₄Each is haloalkyl naturally; And Z is a hydrogen.

In these embodiments, R ₁And R ₂Advantageously each deuterium acute pyogenic infection of nails base and R naturally ₃And R ₄Each trifluoromethyl naturally advantageously.

Particular compound of the present invention comprises: 1, and 25-dihydroxy-21-(2R, 3-dihydroxy-3-methyl-butyl)-20R-cholecalciferol:

1,25-dihydroxy-21-(2R, 3-dihydroxy-3-methyl-butyl)-20S-cholecalciferol:

1,25-dihydroxy-20S-21-(3-hydroxy-3-methyl-butyl)-24-oxo-19-falls-cholecalciferol:

With

1,25-dihydroxy-21 (3-hydroxyl-3-trifluoromethyl-4-three fluoro-butynyl)-26,27-six deuterium generation-20S-cholecalciferols:

In other particular of the present invention, vitamin D compounds is contraction position chemical compound and pharmaceutically useful ester, salt and the prodrug of formula (X):

Wherein:

X ₁Be H ₂Or CH ₂

A ₂Be singly-bound, two key or three key;

R ₁, R ₂, R ₃And R ₄Be C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, for example fluoro-alkyl, for example methyl fluoride and trifluoromethyl;

Z is-OH, Z also can be=O ,-NH ₂Or-SH;

And C ₂₀Configuration be R or S.

In another embodiment, X ₁Be CH ₂In another embodiment, A ₂It is singly-bound.In another embodiment, R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another.In another embodiment, Z is-OH.In another embodiment, X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is-OH.In another embodiment, R ₁, R ₂, R ₃And R ₄Each is methyl naturally.

In another embodiment of the present invention, vitamin D compounds is the geminal chemical compound of following formula:

Above-claimed cpd 33 and 50 chemical name are respectively 1,25-dihydroxy-21-(2R, 3-dihydroxy-3-methyl-butyl)-20R-cholecalciferol and 1,25-dihydroxy-21-(2R, 3-dihydroxy-3-methyl-butyl)-20S-cholecalciferol.

The other embodiments of geminal chemical compound comprise and are used for following vitamin D compounds of the present invention:

(1,25-dihydroxy-21-(2R, 3-dihydroxy-3-methyl-butyl)-20S-19-falls-cholecalciferol),

(1,25-dihydroxy-20S-21-(3-hydroxy-3-methyl-butyl)-24-oxo-19-falls-cholecalciferol),

(1,25-dihydroxy-20S-21-(3-hydroxy-3-methyl-butyl)-24-oxo-cholecalciferol),

(1,25-dihydroxy-21 (3-hydroxyl-3-trifluoromethyl-4-three fluoro-butynyl)-26,27-six deuterium generation-19-fall-the 20S-cholecalciferol)

With

(1,25-dihydroxy-21 (3-hydroxyl-3-trifluoromethyl-4-three fluoro-butynyl)-26,27-six deuterium generation-20S-cholecalciferols).

In other embodiments of the present invention, vitamin D compounds is chemical compound and pharmaceutically useful ester, salt and the prodrug of formula (XI):

Wherein:

X ₁And X ₁Be H independently of one another ₂Or=CH ₂, condition is X ₁And X ₁Not all be=CH ₂

R ₁And R ₂Be hydroxyl, OC (O) C independently of one another ₁-C ₄Alkyl, OC (O) hydroxy alkyl, OC (O) fluoro-alkyl;

R ₃And R ₄Be hydrogen, C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl;

R ₅And R ₆Be C independently of one another ₁-C ₄Alkyl or haloalkyl.

Compatibly, R ₃And R ₄Be hydrogen, C independently of one another ₁-C ₄Alkyl, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl.

In one group of examples of compounds, R ₅And R ₆Be C independently of one another ₁-C ₄Alkyl.

In another group examples of compounds, R ₅And R ₆Be haloalkyl, for example C independently of one another ₁-C ₄Fluoro-alkyl.

Work as R ₃And R ₄With C ₂₀Form C together ₃-C ₆During cycloalkyl, example is a cyclopropyl.

In one embodiment, X ₁And X ₁Each is H naturally ₂In another embodiment, R ₃Be hydrogen, R ₄Be C ₁-C ₄Alkyl.In a preferred embodiment, R ₄It is methyl.

In another embodiment, R ₅And R ₆Be methyl, ethyl, methyl fluoride or trifluoromethyl independently of one another.In a preferred embodiment, R ₅And R ₆Each is methyl naturally.

In another embodiment, R ₁And R ₁Be hydroxyl or OC (O) C independently of one another ₁-C ₄Alkyl.

In a preferred embodiment, R ₁And R ₁Each is OC (O) C naturally ₁-C ₄Alkyl.In another preferred embodiment, R ₁And R ₁Each is acetyl group oxygen base naturally.

An example of this compounds is 1,3-O-diacetyl-1, and 25-dihydroxy-16-alkene-24-oxo-19-falls-cholecalciferol, and it has following array structure:

In another embodiment of the present invention, being used for vitamin D compounds of the present invention is that-20 (S)-1-α, 25-hydroxy-vitamin D fall in 2-methylene-19- ₃:

In WO 02/05823 and US 5,536,713, described the synthetic of this chemical compound and related compound, they have been incorporated herein by reference in full.

In another embodiment of the invention, vitamin D compounds is chemical compound and pharmaceutically useful ester, salt and the prodrug of formula (XII):

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

X ₁And X ₂Be independently of one another H or=CH ₂, condition is X ₁And X ₂Not all be=CH ₂

R ₁And R ₂Be H, OC (O) C independently of one another ₁-C ₄Alkyl (for example OAc), OC (O) hydroxy alkyl, OC (O) haloalkyl; OC (O) C for example ₁-C ₄Alkyl (for example OAc), OC (O) hydroxy alkyl;

R ₃, R ₄And R ₅Be hydrogen, C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl; And

R ₆And R ₇Be C independently of one another _1-4Alkyl or haloalkyl; And

R ₈Be H ,-COC ₁-C ₄Alkyl (for example Ac) ,-the CO hydroxy alkyl or-the CO haloalkyl.

Compatibly, R ₆And R ₇Be haloalkyl independently of one another.Compatibly, R ₈Can represent H or Ac.

In one embodiment, A ₁Be singly-bound, A ₂Be the two keys of singly-bound, E or Z or three key, for example A ₁Be singly-bound and A ₂It is singly-bound.In another embodiment, A ₁Be two keys, A ₂Be two keys of singly-bound, E or Z or three key.Those skilled in the art will readily recognize that and work as A ₂When being three key, R ₅Do not exist.

In one embodiment, X ₁And X ₂Each is H naturally.In another embodiment, X ₁Be CH ₂, X ₂Be H ₂In another embodiment, R ₃Be hydrogen, R ₄Be C ₁-C ₄Alkyl.In preferred embodiments, R ₄It is methyl.

In another embodiment, R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl, for example cyclopropyl.

In another group examples of compounds, R ₁And R ₂Be OH or OC (O) C ₁-C ₄Alkyl, for example R ₁And R ₂All represent OAc.

In one group of examples of compounds, R ₆And R ₇Be C independently of one another _1-4Alkyl.In another group examples of compounds, R ₆And R ₇Be haloalkyl independently of one another.In another embodiment, R ₆And R ₇Be methyl, ethyl or fluoro-alkyl independently of one another, for example they all are methyl.In preferred embodiments, R ₆And R ₈Each is trifluoroalkyl, for example trifluoromethyl naturally.

Compatibly, R ₅Represent hydrogen.

Compatibly, R ₈Represent hydrogen.

In another embodiment, R ₁And R ₂Be OH or OC (O) C ₁-C ₄Alkyl, X ₁Be=CH ₂And X ₂Be H, A ₁Be singly-bound, A ₂Be singly-bound, R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl, R ₅Be hydrogen, R ₆And R ₇Be C independently of one another _1-4Alkyl, and R ₈Be H.In another embodiment, the invention provides purposes, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OH or OAc, R ₃And R ₄With C ₂₀Form cyclopropyl together, and R ₆And R ₇Each is methyl naturally.

Therefore, in certain embodiments, be used for vitamin D compounds of the present invention suc as formula shown in (XII):

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₁And R ₂Be OC (O) C independently of one another ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

R ₃, R ₄And R ₅Be hydrogen, C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl should be understood that and work as A ₂R when being three key ₅Do not exist, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl;

R ₆And R ₇Be alkyl or haloalkyl independently of one another; And

R ₈Be H, C (O) C ₁-C ₄Alkyl, C (O) hydroxy alkyl or C (O) haloalkyl;

And pharmaceutically useful ester, salt and prodrug.

In preferred embodiments, work as A ₁Be singly-bound, R ₃Be hydrogen, R ₄When being methyl, A so ₂Be two keys or three key.

One of preferred chemical compound in background of the present invention, an example of promptly above-mentioned formula (XII) chemical compound is 1,3-two-O-acetyl group-1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-falls-cholecalciferol:

In another preferred embodiment, chemical compound is the chemical compound of formula (XIII), wherein R ₁And R ₂Each is OAc naturally; A ₁Be two keys; A ₂It is three key; And R ₈Be H or Ac:

In some embodiment of the formula of listing in the above (XII), being used for vitamin D compounds of the present invention is suc as formula shown in (XIV):

Other examples of the chemical compound of above-mentioned formula (XIV) comprise:

1,3-two-O-acetyl group-1,25-dihydroxy-23-alkynes-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16,23E-diene-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-cholecalciferol;

1,3,25-three-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-cholecalciferol:

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16,23E-diene-25R-26-three fluoro-cholecalciferols;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol;

1,3,25-three-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-couple of high-19-falls-cholecalciferol;

In some other embodiment of the formula of listing in the above (XII), being used for vitamin D compounds of the present invention is the chemical compound shown in the formula (XV):

In preferred embodiments, X ₁Be=CH ₂And X ₂Be H ₂Work as A ₁Be singly-bound and A ₂When being three key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.Work as A ₁Be singly-bound and A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.Work as A ₁Be two keys and A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.

In another preferred embodiment, X ₁And X ₂Each is H naturally ₂Work as A ₁Be singly-bound and A ₂When being three key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl or haloalkyl.This alkyl is methyl preferably, and this haloalkyl preferably trifluoroalkyl, preferably trifluoromethyl.Work as A ₁Be singly-bound and A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.Work as A ₁Be two keys and A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.

Other examples of above-mentioned formula (XV) chemical compound comprise:

1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-23-alkynes-19-falls-cholecalciferol;

1,3,25-three-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-23-alkynes-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-23Z-alkene-26,27-hexafluoro-19-falls-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-cholecalciferol;

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-20-cyclopropyl-19-falls-cholecalciferol; With

1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-20-cyclopropyl-cholecalciferol.

Preferred formula (XV) chemical compound is 1,3-two-O-acetyl group-1, and 25-dihydroxy-20-cyclopropyl-23E-alkene-26,27-hexafluoro-19-falls-cholecalciferol:

The example of another preferred compound is 1,3-two-O-acetyl group-1, and 25-dihydroxy-20-cyclopropyl-cholecalciferol (being called " compd A "), it has following formula:

" compd A ".

In WO2005/030222, described this compounds, it has been incorporated herein by reference in full.The purposes of the ester and the salt of compd A is also contained in the present invention.Thereby ester comprises hydrolysis in vivo and discharges the pharmaceutically useful unstable ester of compd A.The salt of compd A comprise can with alkali metal and alkaline-earth metal ions and metal cation salt sodium, potassium and calcium ion and salt thereof the adduct and the complex that form such as calcium chloride, malonic acid calcium for example for example.Yet although compd A can be used with the form of its pharmaceutically useful salt or ester, the preferred compd A that adopts itself promptly, does not adopt its ester or salt.

Another chemical compound is to have 1 of following formula, 25-dihydroxy-20,21, and 28-cyclopropyl-cholecalciferol:

This chemical compound is described in US 6,492,353, and it is incorporated herein by reference in full.

The present invention also comprises 1,25-dihydroxy-20,21, the ester of 28-cyclopropyl-cholecalciferol and the purposes of salt.Ester comprises that thereby hydrolysis discharges 1 in vivo, 25-dihydroxy-20,21, the pharmaceutically useful unstable ester of 28-cyclopropyl-cholecalciferol.1,25-dihydroxy-20,21, the salt of 28-cyclopropyl-cholecalciferol comprise can with alkali metal and alkaline-earth metal ions and metal cation salt sodium, potassium and calcium ion and salt thereof the adduct and the complex that form such as calcium chloride, malonic acid calcium for example for example.Yet, although 1,25-dihydroxy-20,21,28-cyclopropyl-cholecalciferol can be used with the form of its pharmaceutically useful salt or ester, preferred employing 1,25-dihydroxy-20,21,28-cyclopropyl-cholecalciferol itself promptly, does not adopt its ester or salt.

In another embodiment, be used for the chemical compound that vitamin D compounds of the present invention is formula (XVI):

Wherein:

X is H ₂Or CH ₂

R ₁Be hydrogen, hydroxyl or fluorine;

R ₂Be hydrogen or methyl;

R ₃Be hydrogen or methyl, condition is to work as R ₂Or R ₃When being methyl, R ₃Or R ₂Must be hydrogen;

R ₄Be methyl, ethyl or trifluoromethyl;

R ₅Be methyl, ethyl or trifluoromethyl;

A is singly-bound or two key;

B is the two keys of singly-bound, E-, the two keys of Z-or three key.

In preferred chemical compound, R ₄And R ₅Each methyl or ethyl naturally, 1-α-fluoro-25-hydroxyl-16 for example, 23E-diene-26,27-two high-20-table-cholecalciferol (being called " compounds X " in an embodiment), it has following formula:

This compounds and synthetic method are described in people such as Radinov, J.Org.Chem.2001,66,6141; People such as Daniewski, US patent 6,255,501; People such as Batcho, among US patent 5,939,408 and the EP808833, its content whole is incorporated herein by reference.1-α-fluoro-25-hydroxyl-16,23E-diene-26,27-two high-20-table-cholecalciferol improved synthesize and be described in hereinafter among the embodiment 1.

Other are used for preferred vitamin D compounds of the present invention and comprise have formula those of (XVII):

Wherein:

B is singly-bound, two key or three key;

X ₁And X ₂Be H independently of one another ₂Or CH ₂, condition is X ₁And X ₂Not all be CH ₂

R ₄And R ₅Be alkyl or haloalkyl independently of one another.

The examples of compounds of formula (XVII) comprises following chemical compound:

1,25-dihydroxy-16-alkene-23-alkynes-20-cyclopropyl-cholecalciferol:

1,25-dihydroxy-16-alkene-23-alkynes-20-cyclopropyl-19-falls-cholecalciferol:

1,25-dihydroxy-16-alkene-20-cyclopropyl-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol:

1,25-dihydroxy-16-alkene-20-cyclopropyl-23-alkynes-26,27-hexafluoro-cholecalciferol:

1,25-dihydroxy-16,23E-diene-20-cyclopropyl-26,27-hexafluoro-19-falls-cholecalciferol:

1,25-dihydroxy-16,23E-diene-20-cyclopropyl-26,27-hexafluoro-cholecalciferol:

1,25-dihydroxy-16,23Z-diene-20-cyclopropyl-26,27-hexafluoro-19-falls-cholecalciferol:

1,25-dihydroxy-16,23Z-diene-20-cyclopropyl-26,27-hexafluoro-cholecalciferol:

1,25-dihydroxy-16-alkene-20-cyclopropyl-19-falls-cholecalciferol:

1,25-dihydroxy-16-alkene-20-cyclopropyl-cholecalciferol:

Another kind of vitamin D compounds of the present invention is 1,25-dihydroxy-21 (3-hydroxyl-3-trifluoromethyl-4-three fluoro-butynyl)-26, and 27-six deuterium generation-19-fall-the 20S-cholecalciferol.

Be used for other preferred vitamin D compounds of the present invention and comprise have formula those of (XVIII):

In preferred embodiments, A ₁Be two keys, X ₁Be=CH ₂And X ₂Be H ₂Work as A ₂When being three key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl or haloalkyl.This alkyl is methyl preferably, and this haloalkyl is trifluoroalkyl preferably, preferably trifluoromethyl.Work as A ₂When being two key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.Also preferred R ₆And R ₇Be alkyl and haloalkyl independently.Work as A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.

In preferred embodiments, A ₁Be two keys, and X ₁And X ₂Each is H naturally ₂Work as A ₂When being three key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl or haloalkyl.This alkyl is methyl or ethyl preferably, and this haloalkyl is trifluoroalkyl preferably, preferably trifluoromethyl.Work as A ₂When being two key, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.Work as A ₂When being singly-bound, preferred R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.

In another embodiment of formula of the present invention (XVIII), R ₁And R ₂Be OC (O) CH ₃, A ₁Be singly-bound and A ₂Be singly-bound, two key or three key, unless work as R ₃Be H and R ₄Be methyl, A ₂Be two keys or three key.In preferred embodiments, R ₃Be H, R ₄Be methyl, R ₅There is not R ₈Be H or C (O) CH ₃, R ₆And R ₇Be alkyl, methyl preferably.

Preferred The compounds of this invention comprises following:

1,3-two-O-acetyl group-1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-falls-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol; 1,3,25-three-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16,23E-diene-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-cholecalciferol; 1,3,25-three-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16,23E-diene-25R, 26-three fluoro-cholecalciferols; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-19-falls-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-19-falls-cholecalciferol; 1,3-two-O-acetyl group-1,25-dihydroxy-16-alkene-23-alkynes-26,27-couple of high-19-falls-cholecalciferol; And 1,3-two-O-acetyl group-1,25-dihydroxy-23-alkynes-cholecalciferol.

These chemical compounds can for example be pressed the described preparation of PCT publication WO2005030222.

Be used for other preferred vitamin D compounds of the present invention and comprise have formula those of (XIX):

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₃, R ₄And R ₅Be hydrogen, C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl;

R ₆And R ₇Be haloalkyl independently of one another; And

R ₈Be H, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

And pharmaceutically useful ester, salt and prodrug.In preferred embodiments, R ₆And R ₇Be three alkylhalide groups, especially trifluoromethyl independently of one another.

These chemical compounds can be for example according to the described preparation of PCT publication WO2005030222, and its content is hereby incorporated by.

The 20-alkyl of geminal for example the vitamin D3 chemical compound of methyl among expection of the present invention.On the one hand, the invention provides the have formula vitamin D of (XX) ₃Chemical compound:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₁, R ₂, R ₃And R ₄Be alkyl, deuterium substituted alkyl, hydroxy alkyl or haloalkyl independently of one another;

R ₅Be halogen, hydroxyl, OC (O) alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

R ₆Be halogen, hydroxyl, OC (O) alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

X ₁Be H ₂Or CH ₂

Y is an alkyl;

And pharmaceutically useful ester, salt and prodrug.

On the one hand, the invention provides the have formula vitamin D of (XX-a) ₃Chemical compound:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₁, R ₂, R ₃And R ₄Be alkyl, hydroxy alkyl or haloalkyl independently of one another;

R ₆Be hydroxyl, OC (O) alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

In some aspects, the invention provides the have formula chemical compound of (XX-b):

Wherein:

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

In other respects, the invention provides the have formula chemical compound of (XX-c):

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

On the other hand, the invention provides the have formula chemical compound of (XX-d):

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

On the other hand, the invention provides the have formula chemical compound of (XX-e):

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

On the other hand, the invention provides the have formula chemical compound of (XX-f):

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

And pharmaceutically useful ester, salt and prodrug.

The preferred chemical compound of the present invention comprises following chemical compound, and it further illustrates in chart 1.The chemical compound of formula (XX) synthetic is included in hereinafter among the embodiment 3-41.

Chart 1

On the other hand, the invention provides the vitamin D of formula XXII ₃Chemical compound:

Wherein: A is singly-bound or two key; B is singly-bound, two key or triple bond; X is H ₂Or CH ₂Y is hydroxyl, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl, OC (O) haloalkyl; Or halogen; Z is hydroxyl, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

And pharmaceutically useful ester, salt and prodrug.

The preferred chemical compound of the present invention is summarized in table 1, the synthetic embodiment 42-50 that is specified in hereinafter of these chemical compounds.

Table 1

Chemical compound	X	Z	Y	A	B
Chemical compound	X	Z	Y	A	B	1,25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol	H ₂	OH	OH	-	-
1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol	H ₂	OAc	OAc	-	-		H ₂	OH	OH	-	-
	H ₂	OAc	OAc	-	-	1,25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols	CH ₂	OH	OH	-	-
1,3-two-O-acetyl group-1,25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols	CH ₂	OAc	OAc	-	-		CH ₂	OH	OH	-	-
	CH ₂	OAc	OAc	-	-	1 α-fluoro-25-hydroxyl-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols	CH ₂	OH	F	-	-
3-O-acetyl group-1 α-fluoro-25-hydroxyl-20-cyclopropyl-cholecalciferol	CH ₂	OAc	F	-	-		CH ₂	OH	F	-	-
	CH ₂	OAc	F	-	-	1,25-dihydroxy-16-alkene-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol	H ₂	OH	OH	＝	-

1,25-dihydroxy-16-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols	CH ₂	OH	OH	＝	-
	CH ₂	OH	OH	＝	-	1 α-fluoro-25-hydroxyl-16-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols	CH ₂	OH	F	＝	-

Having above, the purposes of the chemical compound of given structure extends to its pharmaceutically useful ester, salt and prodrug.

The vitamin D compounds that merits attention especially is a calcitriol.The another kind of vitamin D compounds that merits attention especially is a compounds X.The another kind of vitamin D compounds that merits attention especially is chemical compound Y.

Be used for other examples of compounds as the vitamin D receptor agonist of the present invention and comprise paricalcitol 19-Nor-1,25-dihydroxyvitamin D2 (ZEMPLAR ^TM) (referring to United States Patent (USP) 5,587,497), tacalcitol (BONALFA ^TM) (referring to United States Patent (USP) 4,022,891), degree ostelin (HECTOROL ^TM) (referring to people such as Lam. (1974) Science 186,1038), Maxacalcitol (OXAROL ^TM) (referring to United States Patent (USP) 4,891,364), its salts (DAIVONEX ^TM) (referring to United States Patent (USP) 4,866,048) and falecalcitriol (FULSTAN ^TM).

Other chemical compound comprises ecalcidene, calcithiazol and tisocalcitate.

Other chemical compound comprises atocalcitol, Lexacalcitol and seocalcitol.

Another kind may cause that the chemical compound of concern is secalciferol (" OSTEO D ").

The limiting examples that can be used for other vitamin D compounds of the present invention is included in those that the following international application of having announced describes: WO2006/036813, WO2005/082375, WO2005/030223, WO2005/030222, WO2005/027923, WO2004/098522, WO2004/098507, WO2002/094247, WO98/49138, WO 01/40177, WO0010548, WO0061776, WO0064869, WO0064870, WO0066548, WO0104089, WO0116099, WO0130751, WO0140177, WO0151464, WO0156982, WO0162723, WO0174765, WO0174766, WO0179166, WO0190061, WO0192221, WO0196293, WO02066424, WO0212182, WO0214268, WO03004036, WO03027065, WO03055854, WO03088977, WO04037781, WO04067504, WO8000339, WO8500819, WO8505622, WO8602078, WO8604333, WO8700834, WO8910351, WO9009991, WO9009992, WO9010620, WO9100271, WO9100855, WO9109841, WO9112239, WO9112240, WO9115475, WO9203414, WO9309093, WO9319044, WO9401398, WO9407851, WO9407852, WO9408958, WO9410139, WO9414766, WO9502577, WO9503273, WO9512575, WO9527697, WO9616035, WO9616036, WO9622973, WO9711053, WO9720811, WO9737972, WO9746522, WO9818759, WO9824762, WO9828266, WO9841500, WO9841501, WO9849138, WO9851663, WO9851664, WO9851678, WO9903829, WO9912894, WO9915499, WO9918070, WO9943645, WO9952863, those that in following United States Patent (USP), describe: US3856780, US3994878, US4021423, US4026882, US4028349, US4225525, US4613594, US4804502, US4898855, US4929609, US5039671, US5087619, US5145846, US5247123, US5342833, US5393900, US5428029, US5451574, US5612328, US5747478, US5747479, US5804574, US5811414, US5856317, US5872113, US5888994, US5939408, US5962707, US5981780, US6017908, US6030962, US6040461, US6100294, US6121312, US6329538, US6331642, US6392071, US6452028, US6479538, US6492353, US6537981, US6544969, US6559138, US6667298, US6683219, US6696431, US6774251 and in the following U.S. Patent application of having announced, describe those: US2001007907, US2003083319, US2003125309, US2003130241, US2003171605, US2004167105, US2004214803 and US2005065124.

The structure that should be noted in the discussion above that some The compounds of this invention comprises asymmetric carbon atoms.Therefore, should be appreciated that to comprise the isomer (for example all enantiomer and diastereomer) that produces by this class unsymmetry within the scope of the invention, unless otherwise indicated.Can obtain this class isomer of pure form basically by the isolation technics of classics and/or by the synthetic of spatial chemistry control.

Naturally occurring or synthetic isomer can be separated with multiple mode known in the art.The method of separating the racemic mixture of two kinds of enantiomer comprises the chromatography (for example W.J.Lough edits .Chapman andHall referring to " Chiral Liquid Chromatography, ", New York (1989)) that adopts chiral stationary phase.Also can be by classical disassemble technique enantiomer separation.For example, can utilize formation diastereoisomeric salt and Steppecd crystallization to come enantiomer separation.For the carboxylic acid Separation of Enantiomers, for example brucine, quinine, ephedrine, strychnine etc. generate diastereoisomeric salts to chiral base that can be by adding enantiomer-pure.Perhaps, can with the chiral alcohol of enantiomer-pure for example menthol generate non-enantiomer ester, separate non-enantiomer ester and hydrolysis then, obtain the carboxylic acid of free enantiomer enrichment.For the separation of amino-compound optical isomer, for example camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can cause the generation of diastereoisomeric salt to add chiral carboxylic acids or sulfonic acid.

The present invention also provides pharmaceutical composition, and it comprises the vitamin D compounds as herein described and the pharmaceutically useful carrier of effective dose.In further embodiment, effective dose is the amount of effective Film with Preventing Adhesion, as mentioned before.

In one embodiment, use pharmaceutically useful preparation that vitamin D compounds is applied to individuality, described pharmaceutically useful formulation example as, can be after it is applied to individuality to individuality continue to send vitamin D compounds at least 12 hours, 24 hours, 36 hours, 48 hours, a week, two weeks, three weeks or pharmaceutically useful preparation all around.

In certain embodiments, these pharmaceutical compositions are suitable for the part or by oral administration to individuality, perhaps use to individual intraperitoneal.In other embodiments, as hereinafter described in detail, pharmaceutical composition of the present invention can be mixed with especially with solid or liquid form and be used, comprise those that are fit to following approach: (1) is Orally administered, for example Haust (drench) (aqueous or nonaqueous solution or suspension), tablet, bolus, powder, granule, paste; (2) parenteral administration, for example subcutaneous, intramuscular or intravenous injection are for example with aseptic solution or suspension form; (3) topical application for example is applied to ointment, ointment or the spray of skin; (4) intravaginal or internal rectum, for example vaginal suppository, ointment or foam; (5) aerosol, for example water-borne aerosol, Liposomal formulation or contain the solid particle of chemical compound; Perhaps (6) intraperitoneal is sent, for example with aseptic solution or suspension form (for example aqueous solution or suspension).

Wording " pharmaceutically useful " expression those vitamin D compounds of the present invention, the compositions that contains this compounds and/or dosage form, it reasonably is being suitable for contacting, not having over-drastic toxicity, stimulation, allergy or other problem or complication with human and animal's tissue, have rational interests/the risk ratio in the medical judgment scope.

Wording " pharmaceutically useful carrier " comprises pharmaceutically useful material, composition or solvent, for example liquid or solid filler, diluent, excipient, solvent or encapsulating material, their participate in the purpose chemicals are carried or are transported to from organ of body or part another organ or another part of body.Every kind of carrier must be " acceptable ", and its meaning is compatible and harmless to the patient with other composition of preparation.The example that can be used as some materials of pharmaceutically useful carrier comprises: (1) saccharide, for example lactose, dextrose plus saccharose; (2) starch, for example corn starch and potato starch; (3) cellulose and derivant thereof, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Powdered tragakanta; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Pulvis Talci; (8) excipient, for example cocoa butter and suppository wax; (9) oils, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, sunflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycol, for example propylene glycol; (11) polyhydric alcohol, for example glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) esters, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's mixture; (19) ethanol; (20) phosphate buffered solution; (21) be used for other nontoxic, compatible material of pharmaceutical preparation.

In compositions, also can there be wetting agent, emulsifying agent and lubricant, for example sodium lauryl sulphate and magnesium stearate, and coloring agent, releasing agent, coating materials, sweeting agent, correctives and aromatic, antiseptic and antioxidant.

The example of pharmaceutically useful antioxidant comprises: (1) water soluble antioxidant, for example ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite etc.; (2) oil-soluble inhibitor, for example ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol etc.; (3) metal-chelator, for example citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid etc.

Compositions can be presented with unit dosage form easily, and can be prepared by the well-known method of any pharmaceutical field.

The amount that can form the active component of single dosage form with carrier mass combination will be along with the individuality of accepting administration and specific method of application and different.The amount that can form the active component of single dosage form with the carrier mass combination generally is the amount that this chemical compound produces preventive effect.Generally speaking, in one of percentage hundred, this amount is about 0.1% to about 99% active component, and preferred about 5% to about 70%, most preferably from about 10% to about 30%.

Prepare these method for compositions and comprise the step that vitamin D compounds and carrier and one or more optional auxiliary elements are combined.Generally speaking, preparation prepares by the following method: the two evenly and closely combines with the solid carrier of vitamin D compounds and liquid-carrier or fine pulverizing or this, then if necessary, product is shaped.

Being suitable for Orally administered compositions of the present invention can be capsule, cachet, pill, tablet, lozenge (uses the substrate of flavoring, be generally sucrose and arabic gum or tragakanta), powder, the form of granule, or solution in aqueous or non-aqueous liquid or suspension form, or the form of oil-in-water type or water-in-oil emulsion, or the form of elixir or syrup, or pastille (uses inert base, for example gelatin and glycerol, perhaps sucrose and arabic gum) and/or form such as collutory, they contain the vitamin D compounds of scheduled volume separately as active component.Chemical compound also can be used with the form of big nine doses, electuary or paste.

Be used for Orally administered solid dosage forms of the present invention (capsule, tablet, pill, dragee, powder, granule etc.), active component mixes with one or more pharmaceutically useful carriers, for example sodium citrate or dicalcium phosphate, and/or any following ingredients: (1) filler or extender, for example starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or arabic gum; (3) wetting agent, for example glycerol; (4) disintegrating agent, for example agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate; (5) dissolving blocker, for example paraffin; (6) absorb accelerator, for example quaternary ammonium compound; (7) wetting agent, for example acetyl alcohol and glyceryl monostearate; (8) absorbent, for example Kaolin and bentonite; (9) lubricant, for example Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and its mixture; (10) coloring agent.Under the situation of capsule, tablet and pill, pharmaceutical composition can also comprise buffer agent.The solid composite that also can adopt similar type uses excipient for example lactose or lactose (milk sugar) as the filler in soft and the hard-filled gelatin capsule agent, and high molecular weight polyethylene glycol etc.

Tablet can randomly contain one or more auxiliary elements by compacting or mechanography preparation.Compressed tablet can use binding agent (for example gelatin or hydroxypropyl emthylcellulose), lubricant, inert diluent, antiseptic, disintegrating agent (for example primojel or cross-linking sodium carboxymethyl cellulose), surfactant or dispersant to be prepared.Molded tablet can by in the machine that is fit to carrying out molded the preparation with the moistening Powdered mixture of active principles of inert liquid diluent.

The tablet of pharmaceutical composition of the present invention and other solid dosage formss for example dragee, capsule, pill and granule can randomly have indentation or have coating and shell, for example well-known other coatings in enteric coating and the field of pharmaceutical preparations.For example also can use the hydroxypropyl methylcellulose of different proportion (so that required releasing properties to be provided), other polymeric matrixs, liposome and/or microsphere that they are prepared, so that the wherein slow release or the controlled release of active component to be provided.They can be sterilized, and method is for example to filter by the filter of holding back antibacterial, perhaps mixes biocide with the form of aseptic solid composite before use, and it dissolves in sterilized water or some other aseptic injectable medium.These compositionss can also randomly contain opacifier, and can be randomly with delayed mode only in a gastrointestinal part or preferentially discharge composition of active components in a gastrointestinal part.The example of operable embedding composition comprises polymeric material and wax class.

Active component also can be the form of microencapsulation, if suitably, also has one or more above-mentioned excipient.

The Orally administered liquid dosage form that is used for of vitamin D compounds comprises pharmaceutically useful Emulsion, microemulsion, solution, suspension, syrup and elixir.Except active component, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzoic acid benzyl ester, propylene glycol, 1, the fatty acid ester of 3-butanediol, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, oxolane, Polyethylene Glycol and anhydro sorbitol, with and composition thereof.

Except inert diluent, Orally administered composition can also comprise adjuvant, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives, coloring agent, aromatic and antiseptic.

Except active vitamin D compounds, suspension can also contain suspending agent, for example ethoxylation isooctadecanol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, inclined to one side aluminium hydroxide, bentonite, agar and tragakanta and composition thereof.

The pharmaceutical composition of the present invention that is used for rectum or vaginal application can be the form of suppository, it can mix by the non-irritating excipient that one or more vitamin D compounds and one or more are suitable or carrier (for example comprise cocoa butter, Polyethylene Glycol, suppository with wax or Salicylate) and prepare, it at room temperature is a solid, but under body temperature, be liquid, therefore will in rectum or vaginal canal, melt and discharge active component.

The compositions of the present invention that is suitable for vaginal application also comprises vaginal suppository, tampon, ointment, gel, paste, foam or spray, and they contain appropriate carrier known in the art.

The dosage form that is used for part or transdermal administration vitamin D compounds comprises powder, spray, ointment, paste, ointment, lotion, gel, solution, patch and inhalant.Active vitamin D compounds can be mixed with pharmaceutically useful carrier and any antiseptic, buffer agent or the propellant that might need under aseptic condition.

Except vitamin D compounds of the present invention, ointment, paste, ointment and gel can also contain excipient, for example animal and plant fat, oils, wax class, paraffin, starch, tragakanta, cellulose derivative, Polyethylene Glycol, silicone, bentonite, silicic acid, Pulvis Talci and zinc oxide, or its mixture.

Except vitamin D compounds, powder and spray can also contain excipient, for example lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, the perhaps mixture of these materials.Spray can contain propellant commonly used in addition, for example chloro-fluoro-carbon kind and volatile unsubstituted hydrocarbon, for example butane and propane.

Perhaps, vitamin D compounds can be used by aerosol.This is to realize by water-borne aerosol, Liposomal formulation or solid particle that preparation contains this chemical compound.Also can use the suspension of non-aqueous (for example fluorocarbon propellant).Sound wave aerosol apparatus preferably, because the minimum shear forces that they are subjected to medicine, and shear the degraded that can cause chemical compound.

Usually, water-borne aerosol is that aqueous solution or suspension by compounding pharmaceutical and conventional pharmaceutically useful carrier and stabilizing agent prepares.Carrier and stabilizing agent are different because of the needs of specific compound, but generally include non-ionic surface active agent (tween, general stream Buddhist nun gram or Polyethylene Glycol), harmless protein such as serum albumin, Isosorbide Dinitrate, oleic acid, lecithin, aminoacid such as glycine, buffer agent, salt, sugar or sugar alcohol.Aerosol is generally prepared by isosmotic solution.

The attendant advantages that provides the control of vitamin D compounds to send to body is provided transdermal patch.This class dosage form can be by with medicine dissolution or be dispersed in the appropriate medium and prepare.Also can use absorption enhancer, cross over the flux of skin to increase active component.By rate controlling membranes being provided or active component being dispersed in polymeric matrix or the gel, can control the speed of this class flux.

Be suitable for the pharmaceutical composition of the present invention that parenteral or intraperitoneal use and comprise one or more vitamin D compounds and one or more pharmaceutically useful sterile isotonic aqueous or non-aqueous solution, dispersion, suspension or emulsion, perhaps sterilized powder, described powder can be reconfigured as the solution or the dispersion of sterile injectable before being about to use, they can contain antioxidant, buffer agent, antibacterial, make preparation and expection receiver's the isoosmotic solute of blood or suspending agent or thickening agent.

The compositions that comprises vitamin D compounds of the present invention can comprise the material that increases composition viscosity suitably, especially for promoting compositions when the intraperitoneal administration and organizing the time of contact that contacts or increase the two.

The aqueous that is fit to that can adopt in pharmaceutical composition of the present invention and the example of non-aqueous carrier comprise for example olive oil and injectable organic ester ethyl oleate for example of water, ethanol, polyhydric alcohol (for example glycerol, propylene glycol, Polyethylene Glycol etc.) and suitable mixture thereof, vegetable oil.Can be for example by utilize coating material such as lecithin, under the situation of dispersion by keeping required particle diameter and by utilizing surfactant to keep suitable flowability.

These compositionss also can contain adjuvant, for example antiseptic, wetting agent, emulsifying agent and dispersant.By comprising various antibacteriums and antifungal for example p-Hydroxybenzoate, methaform, phenol, sorbic acid etc., can guarantee to avoid action of microorganisms.Also may in compositions, comprise isotonic agent as sugar, sodium chloride etc.In addition, for example aluminum monostearate and gelatin can realize that the delay of injectable medicament forms absorbs by comprising the material that postpone to absorb.

In some cases, for the effect of prolong drug, need delay the absorption of medicine from subcutaneous or intramuscular injection agent.Utilize the crystallization of poorly water-soluble or the liquid suspension of amorphous materials can realize this point.Therefore the absorption rate of medicine depends on its rate of dissolution, and the latter then may depend on crystal size and crystal form.

Perhaps, by medicine dissolution or the delay that is suspended in the medicament forms of realizing parenteral in the oiliness solvent are absorbed.

Injectable reservoir type is to prepare by the microcapsule substrate that for example forms vitamin D compounds at biodegradable polymer in polyactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester.According to the character of the ratio of medicine and polymer and used particular polymers, speed that can control drug release.The example of other biodegradable polymer comprises poly-(ortho esters) and poly-(anhydride).The reservoir devices injectable formulation also prepares by pharmaceutical pack being embedded in liposome compatible with body tissue or the microemulsion.

The present invention also provides the medicine box of Film with Preventing Adhesion.In one embodiment, described medicine box comprises the vitamin D compounds of the effective dose of unit dosage form, and the description that is used for using to the individuality of easy trouble adhesion vitamin D compounds.

In preferred embodiments, described medicine box comprises the sterile chamber that has held vitamin D compounds; This class container can be box, ampoule, bottle, bottle, test tube, bag, pouch, blister package or other suitable forms known in the art.This class container can be made by the material that plastics, glass, thin paper, metal forming or other are fit to hold medicine.

In general described description includes the information of the purposes of related compounds Film with Preventing Adhesion; In preferred embodiments, description comprises following at least a: chemical compound is described; The administration and the dosage schedule that are used for Film with Preventing Adhesion; Points for attention; Warning; Indication; Contraindication; The information of overdose; Untoward reaction; Animal pharmacology; Clinical research; And/or list of references.Description can directly be printed on the container (if present), perhaps as the label that is used for container, perhaps with independent paper, pamphlet, card or file, provides in container or with container.

When vitamin D compounds is applied to humans and animals as medicine, they can give with itself or with the form of pharmaceutical composition, described compositions for example contains 0.1 to 99.5% active component and the pharmaceutically useful carrier of (more preferably 0.5 to 90%).

Regardless of selected route of administration, all can vitamin D compounds of the present invention (it can use suitable hydrated form) and/or pharmaceutical composition be mixed with pharmaceutically useful dosage form by conventional method well known by persons skilled in the art.

Can change actual dose level and the time of application of active component in pharmaceutical composition of the present invention, to obtain that specific patient, compositions and method of application are effectively reached required treatment response and the active principle nontoxic to the patient.A kind of dosage range of illustrative is 0.1-300 μ g/ days.

The preferred dose of vitamin D compounds of the present invention is the maximum that the patient can tolerate and not cause hypercalcemia.Preferably, use vitamin D compounds of the present invention with following concentration: about 0.001 μ g is to about 100 μ g/ kg body weight, the about 100 μ g/kg body weight of the about 10 μ g/kg body weight of about 0.001-or about 0.001 μ g-.Scope within the numerical value of above quoting also is a part of the present invention.For example, another conventional dosage can be 0.1-600 μ g/kg, for example 1-100 μ g/kg.

Described vitamin D compounds can carry out separately, successively or administration simultaneously with the pharmaceutical preparation that separates or merge with second medicine that prevents and/or treats adhesion (for example second kind vitamin D compounds of the present invention or antibiotic or anti-inflammatory compound).This class combined therapy can increase the effectiveness of whole treatment, perhaps can allow to use second medicine of comparing lower amount when not having vitamin D compounds.In the situation of prevention postoperative intestinal adhesion, can be expected at operation before, for example administration of antibiotics or anti-inflammatory compound before 24 hours, it typically is general administration (for example oral administration), so that when operation, reach effective blood plasma (or partial) level.

Vitamin D compounds of the present invention is not suitable for and crosslinked composition or crosslinkable composition co-administered or common preparation, described composition reacts to each other in aqueous environments and forms three-dimensional substrate, the dry powder composition of homogeneous for example, it comprises: first kind of component, have the core that is replaced by m nucleophilic group, wherein m is more than or equal to 2; Second kind of component has the core that is replaced by n electrophilic group, and wherein n is more than or equal to 2, and m+n is greater than 4; Wherein said nucleophilic group and electrophilic group right and wrong in dry environment are reactive, but will become reactive group in case be exposed in the aqueous environments, to such an extent as to these components react to each other, form three-dimensional substrate (referring to US2005/0281883) in aqueous environments.

When the formation of adhesion was relevant with specific potential disease or disease, the vitamin D compounds that is used for Film with Preventing Adhesion can or prevent the other drug of described potential disease or disease to use with treatment.

In the situation of prevention postoperative intestinal adhesion, dosage regimen is used vitamin D compounds before being included in operation capapie easily, and is for example Orally administered.Perhaps, vitamin D compounds can be to the direct local application of operative site (for example being administered to peritoneum by the intraperitoneal approach) when operation finishes.Compatibly, vitamin D compounds can with controlled release forms when operation finishes to the direct local application of operative site, so that (for example in several days) realize partial successive administration in a period of time.

The solution of described vitamin D compounds can be used for before operation, perform the operation or operation back cleaning operative site.

Compatibly, described vitamin D compounds general before operation is used, and is for example Orally administered, in addition, vitamin D compounds when operation finishes to directly local application of operative site (for example peritoneum).

In case operation finishes (for example be about to sew up the incision before), the compositions that comprises vitamin D compounds (for example waterborne compositions) that can pour into certain volume to operative site.Volume is that 100-2000ml, for example 1000ml may be fit to.

Synthesizing of The compounds of this invention

Synthetic existing in the art description of The compounds of this invention, for example at WO2006/036813, WO2005/082375, WO2005/030223, WO2005/030222, WO2005/027923, WO2004/098522, WO2004/098507, WO2002/094247, WO98/49138, US6,492,353, US 6,030,962 and U.S.5,939, description is arranged in 408, and its content whole is incorporated herein by reference.

The embodiment of the invention

To the present invention be described by embodiment now with reference to following indefiniteness.

Synthetic embodiment

All relate to vitamin D ₃The operation of analog is all being carried out under nitrogen in the amber glass vessel.Before using benzophenone sodium with oxolane from wherein steaming, and with the solution of dried over sodium sulfate solute.Fusing point is measured on Thomas-Hoover capillary detection instrument and is not proofreaied and correct.Optical rotation is measured down at 25 ℃.Except as otherwise noted, otherwise ¹H NMR composes under 400MHz at CDCl ₃Middle record.TLC carries out on silica gel plate (Merck PF-254), range estimation or spray on plank and heat afterwards and estimate with the methanol solution of 10% phosphomolybdic acid under short wavelength's UV light.Flash chromatography carries out on 40-65 μ m order silica gel.Preparation HPLC flow velocity with 100ml/min on 5 * 50cm post and 15-30 μ m order silica gel carries out.

Embodiment 1

1-α-fluoro-25-hydroxyl-16,23E-diene-26,27-two high-the synthesizing of 20-table-cholecalciferol

The tert-butyl group-dimethyl-(4-methylene-3-{2-[7a-methyl isophthalic acid-(1,4, the 5-trimethyl-oneself-the 2-thiazolinyl)-octahydro-indenes-4-subunit]-the second subunit }-cyclohexyl oxygen base)-silane

To the 4-methylene-3-{2-[7a-methyl isophthalic acid-(1 that stirred, 4, the 5-trimethyl-oneself-the 2-thiazolinyl)-octahydro-indenes-4-subunit]-the second subunit }-Hexalin (100.00g, 0.25mol) the continuous imidazoles (40.80g that adds in the solution of DMF (250mL), 0.6mol) and (tert-butyl group dimethyl) silylation chloride (45.40g, 0.3mol).At room temperature stirred this reactant mixture 1 hour, with hexane (750mL) dilution, water (500mL), 1N HCl (500mL), saline (500mL) washing and through Na ₂SO ₄Dry.Residue behind the evaporating solvent (155g) is filtered by silicagel column (500g, the hexane solution of 5%AcOEt), obtain title compound (115.98g, 0.23mol, 92%).

¹H-NMR: δ 0.04 and 0.08 (2s, 6H), 0.59 (s, 3H), 0.90 (d, 3H, J=6.6Hz), 0.92 (d, 3H, J=6.6Hz), 0.98 (s, 9H), 0.99 (d, 3H, J=7.0Hz), 1.06 (d, 3H, J=6.8Hz), 1.10-2.95 (m, 21H), 5.11 (br s, 2H), 5.22 (m, 2H), 6.49 (br s, 2H).

2-[5-(tert-butyl group-dimethyl-silanyloxy base)-2-methylene-ring caproic subunit]-ethanol and 1-(2-hydroxyl-1-methyl-ethyl)-7a-methyl-octahydro-indenes-4-alcohol

Under-55 to-60 ℃, streams of ozone is fed the tert-butyl group-dimethyl-(the 4-methylene-3-{2-[7a-methyl isophthalic acid-(1 that stirred, 4, the 5-trimethyl-oneself-the 2-thiazolinyl)-octahydro-indenes-4-subunit]-the second subunit-cyclohexyl oxygen base)-silane (23.4g, 45.8mmol), pyridine (5.0mL) and sudan red 7B (15.0mg) in the solution of dichloromethane (550mL) until tonyred decolour (55 minutes).(6.75g, 180mmol) back adds ethanol (250mL) to add sodium borohydride.Reactant is heated to room temperature and at room temperature stirring 1 hour.Add acetone (15mL), add saline (300mL) after 30 minutes.Mixture washs with ethyl acetate (500mL) dilution and water (600mL).Water extracts with AcOEt (300mL).The organic facies Na that merges ₂SO ₄Dry.Behind the evaporating solvent, residue (26.5g) filters through silicagel column (500g, the hexane solution of 15%, 30% and 50% AcOEt), obtains: (5.9g comprises the mixture (NMR detects about 83% purity) that required A encircles to flow point A ¹H NMR: δ 5.38 (1H, t, J=6.4Hz), 4.90 (1H, brs), 4.57 (1H, brs), 4.22 (1H, dd, J=7.3,12.5Hz), 4.13 (1H, dd, J=6.3,12.5Hz), 3.78 (1H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s); Flow point A is used for the synthetic of A ring precursor.Flow point B (14.6g, the CD that comprises oxidation in various degree encircles segmental mixture).Flow point B is further carried out ozonolysis to obtain the Lythgoe glycol.Continue 30 minutes (tonyred decolouring) in the flow point B (14.6g) that under-55 to-60 ℃, the streams of ozone feeding was stirred and ethanol (225mL) solution of sudan red 7B (3.0mg).(3.75g 100mmol) and with reactant heats to room temperature, at room temperature stirs 1 hour to add sodium borohydride.Add acetone (5mL), add saline (200mL) after 30 minutes.Dilute this mixture and wash (250mL) with water with dichloromethane (300mL).Water extracts with dichloromethane (200mL).The organic facies that merges is evaporated to dried (decline is evaporated with the 100ml toluene of adding).Residue (16.2g) is dissolved in the dichloromethane (100mL), is concentrated into about 20mL volume, with crystallization in petroleum ether (30mL) dilution and the placement refrigerator.Leach white powder (4.05g), mother solution is concentrated and through silica gel (100g, the CH of 5%MeOH ₂Cl ₂Solution) filter, obtain yellow oil (9.4g), its recrystallization (20mL, dichloromethane: petroleum ether 1: 2), obtain white powder (1.79g).Therefore the total output of Lythgoe glycol is that (5.84g, 27.5mmol press D ₂Calculating productive rate is 60%) ¹H NMR: δ 4.08 (1H, m), 3.64 (1H, dd, J=3.3,10.6Hz), 3.39 (1H, dd, J=6.6,10.6Hz), 2.04-1.14 (15H, m), 1.03 (3H, d, J=6.6Hz), 0.96 (3H, s).

1-(2-hydroxyl-1-methyl-ethyl)-pure and mild 1-of 7a-methyl-octahydro-indenes-4-(2-hydroxyl-1-methyl-ethyl)-7a-methyl-octahydro-indenes-4-alcohol

With the tert-butyl group-dimethyl-(4-methylene-3-{2-[7a-methyl isophthalic acid-(1,4, the 5-trimethyl-oneself-the 2-thiazolinyl)-octahydro-indenes-4-subunit]-the second subunit }-cyclohexyl oxygen base)-silane (98.8g, 249mmol) be dissolved in dichloromethane (900mL) and the ethanol (400mL), add pyridine (25.0mL) and sudan red 7B (30.0mg) and this mixture is cooled to-65 to-70 ℃.(until the tonyred decolouring, reaction also can be monitored by TLC, and the tonyred decolouring is corresponding to vitamin D to feed streams of ozone lasting 3 hours ₂Consumption).Add sodium borohydride (24.0g 0.64mol), heats this reactant to room temperature and at room temperature stirring 1 hour in batches.Add acetone (75mL) (keeping temperature to be lower than 35 ℃) also stores this reactant mixture and spends the night in batches in refrigerator.Water (600mL) washs this mixture.(6 * 300mL) extract water with dichloromethane.The organic facies that merges is through Na ₂SO ₄Dry.Residue behind evaporating solvent (118g) obtains through silicagel column (0.5kg, the hexane solution of 30%, 50% AcOEt) purification: flow point A (69.7g, CD-ring plate section); Flow point B (from hexane: AcOEt 3: 1, obtaining the pure Lythgoe glycol of 4.8g after the crystallization); Flow point C (from AcOEt, obtaining the pure raw materials of compound of 12.3g after the crystallization); Flow point D (11.5g, described raw material and 4-methylene-cyclohexane extraction-1,3-glycol).

Further flow point A is carried out ozonolysis to obtain described glycol.In the solution of ethanol (500mL), dichloromethane (600mL) and sudan red 7B (3.0mg), continue 3 hours (tonyred decolouring) at the flow point A (69.7g) that under-65 to-70 ℃ the streams of ozone feeding was stirred.(22.5g 0.6mol), heats this reactant to room temperature and at room temperature stirred 1 hour to add sodium borohydride.Add acetone (125mL) (maintaining the temperature at below 35 ℃) in batches and this reactant mixture stored in refrigerator and spend the night.Water (600mL) washs this mixture.With dichloromethane (2 * 300mL) and AcOEt (300mL) aqueous phase extracted.The organic facies that merges is through Na ₂SO ₄Drying also is evaporated to dried.(AcOEt: purification hexane 1: 2) obtains residue (55.0g): flow point E (the crystallization glycol that 15.7g is pure) by crystallization; Flow point F (35g comprises the mixture of Lythgoe glycol).Flow point F (35g) is by silicagel column (0.5kg, 30%, the hexane solution of 50%AcOEt) purification, crystallization (AcOEt: obtain flow point G (18.9g) hexane 1: 2), therefore the total output of described glycol is 39.4g, is 74.5% by the parent material productive rate).

¹H NMR：δ5.38(1H，t，J＝6.4Hz)，4.90(1H，brs)，4.57(1H，brs)，4.22(1H，dd，J＝7.3，12.5Hz)，4.13(1H，dd，J＝6.3，12.5Hz)，3.78(1H，m)，2.40-1.30(6H，m)，0.83(9H，s)，0.01(3H，s)，0.00(3H，s)；

Flow point D (11.5g) obtains (in crystallization (AcOEt) back) by silicagel column (0.3kg, the hexane solution of 50%AcOEt) purification: flow point H (1-that 1.1g is pure (2-hydroxyl-1-methyl-ethyl)-7a-methyl-octahydro-indenes-4-alcohol crystallization, 2.8%); Flow point I (10.2g, the mixture of required compound).Therefore the total output of isolating (S)-(Z)-3-(2-hydroxyl-second subunit)-4-methylene-Hexalin is 13.4g, 34.8%.

¹H NMR：δ5.51(1H，t，J＝6.6Hz)，5.03(1H，brs)，4.66(1H，brs)，4.24(2H，m)，，3.94(1H，m)，2.55(1H，dd，J＝3.9，13.2Hz)，2.41(1H，m)，2.25(1H，dd，J＝7.8，12.9Hz)，1.94(1H，m)，1.65(1H，m)。

(S)-(Z)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-2-methylene-ring caproic subunit]-ethanol

To (S)-(the Z)-3-that stirred (2-hydroxyl-second subunit)-4-methylene-Hexalin (4.04g, 26.3mmol) the continuous imidazoles (5.36g that adds in the solution of dichloromethane (40mL), 78.7mmol) and (tert-butyl group dimethyl) silylation chloride (9.50g, 63.0mmol).At room temperature stirred this reactant mixture 100 minutes.Add entry (25mL) then.After 15 minutes, (350mL) dilutes this mixture with hexane, water (2 * 100mL) and saline (50mL) wash and use Na ₂SO ₄Dry.Behind the evaporating solvent residue (10.7g) is dissolved in oxolane (50mL), adds Bu down at+5 ℃ ₄(26.5mL 1M/THF) and at+5 ℃ stirred these mixture 45 minutes to NF, then restir 30 minutes at room temperature.Water (100mL) and ethyl acetate (250mL) are diluted this mixture.After separating organic layer, water (100mL) and saline (50mL) washing.(5 * 50mL) extract water layer with ethyl acetate.The organic layer Na that merges ₂SO ₄Dry.Behind the evaporating solvent with residue through FC (150g, 10%, 50% and the solution of 100%AcOEt in hexane) purification, obtain title compound.(6.43g, NMR purity 85%, title compound productive rate 78%)

¹H NMR：δ5.38(1H，t，J＝6.4Hz)，4.90(1H，brs)，4.57(1H，brs)，4.22(1H，dd，J＝7.3，12.5Hz)，4.13(1H，dd，J＝6.3，12.5Hz)，3.78(1H，m)，2.40-1.30(6H，m)，0.83(9H，s)，0.01(3H，s)，0.00(3H，s)。

Synthesizing of A ring precursor

(2R, 3S, 7S)-[7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-yl]-methanol

At room temperature to thick (S)-(Z)-2-[5-(tert-butyl group dimethyl) the silanyloxy base that stirred)-2-methylene-ring caproic subunit]-ethanol (5.9g, about 18.3mmol, the flow point A that obtains from ozonolysis) the solution of dichloromethane (120mL), adds AcONa (2.14g, 26.1mmol), add then 72% mCPBA (4.32g, 18.0mmol).This reactant mixture was stirred 1/2 hour down at 10 ℃, use hexane (200mL) dilution then and with 10% K ₂CO ₃(3 * 150mL) washings, and use Na ₂SO ₄Dry.Residue behind the evaporating solvent (6.6g) filters through silicagel column (150g, the 10%AcOEt solution in hexane) and obtains thick title compound (4.87g, about 15.4mmol, 84%). ¹H-NMR: δ 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J=5.6Hz), 3.60 (m, 2H), 3.86 (m, 1H), 4.91 (m, 1H).

Benzoic acid (2R, 3S, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester

At room temperature to the (2R that stirred, 3S, 7S)-[7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-yl]-methanol (4.87g, about 15.4mmol) in the solution of pyridine (25mL), adds Benzenecarbonyl chloride. (2.14mL, 18.4mmol), and stirred this reactant mixture 1 hour.Add entry (25mL) and at room temperature stir after 45 minutes and dilute this mixture, use saturated NaHCO with hexane (80mL) ₃Solution (50mL) washing, and use Na ₂SO ₄Dry.Residue behind the evaporating solvent (17.5g) obtains title compound (5.44g, 14.0mmol, 91%) through FC (150g, the 10%AcOEt solution in hexane) purification. ¹H NMR：δ8.04-7.80(2H，m)，7.56-7.50(1H，m)，7.44-7.37(2H，m)，4.94(1H，brs)，4.92(1H，brs )，4.32(1H，dd，J＝4.8，11.9Hz)，4.14(1H，dd，J＝6.2，11.9Hz)，3.83(1H，m)，3.21(1H，dd，J＝4.8，6.2Hz)，2.42(1H，m)，2.04-1.90(3H，m)，1.64-1.34(2H，m)，0.83(9H，s)，0.02(3H，s)，0.01(3H，s)。

Benzoic acid (2R, 3S, 5R, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-5-hydroxyl-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester

Under 85 ℃ to the benzoic acid (2R that stirred, 3S, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester (10.0g, 25.7mmol add selenium dioxide (3.33g in the solution of) Zai diox (550mL), 30.0mmol), add tert-butyl hydroperoxide (9.0mL then, 45.0mmol, the solution of 5-6M in nonane), and this reactant mixture stirred 16 hours at 85 ℃, add selenium dioxide (1.11g subsequently, 10.0mmol), add tert-butyl hydroperoxide (3.0mL, 15.0mmol then, the solution of 5-6M in nonane) after, with this reactant mixture 85 ℃ of restir 6 hours.Under vacuum,, obtain: the mixture (8.7g) of initiation material (970mg, 10%) and epimer a and epimer b except that desolvating and residue (15.3g) being filtered through silicagel column (300g, the 20%AcOEt solution in hexane).This mixture is divided into 3 parts (every part 2.9g), through FC (200g, the solution of 5% isopropyl alcohol in hexane, whole six chromatographic isolation are used identical chromatographic column) twice of purification, obtain: epimer b (1.83g, be 10: 1 mixture of 10b: 10a, about 16% 5 'alpha '-hydroxylation compounds); Epimer a (6.0g, 14.8mmol, 58%) is white crystal.The structure of epimer a confirms by the X-radiocrystallography.

¹H NMR：δ8.02-7.90(2H，m)，7.58-7.50(1H，m)，7.46-7.38(2H，m)，5.25(1H，br s)，5.11(1H，br s)，4.26(1H，dd，J＝5.5，12.1Hz)，4.15(1H，dd，J＝5.9，12.1Hz)，4.07(1H，m)，3.87(1H，m)，3.19(1H，dd，J＝5.5，5.9Hz)，2.34-1.10(5H，m)，0.81(9H，s)，0.01(3H，s)，0.00(3H，s)。

Benzoic acid (2R, 3S, 5S, 7R)-7-(tert-butyl group dimethyl) silanyloxy base)-5-fluoro-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester

Under-75 ℃ to diethylamino sulfur trifluoride (the DAST) (2.0mL that stirred, 16.0mmol) in the solution of trichloroethylene (20mL), add benzoic acid (2R, 3S, 5R, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-5-hydroxyl-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester (2.78g, 6.87mmol) solution in trichloroethylene (126mL).Add methanol (5.5mL)-75 ℃ of stirrings after 20 minutes, add saturated NaHCO then ₃Solution (6mL), and, use saturated NaHCO with hexane (150mL) dilution gained mixture ₃Na is used in solution (100mL) washing ₂SO ₄Dry and concentrated.Residue (4.5g) obtains title compound (2.09g, 5.14mmol, 75%) through FC (150g, DCM: hexane: AcOEt are 10: 20: 0.2) purification ¹H NMR: δ 8.02-7.99 (2H, m), 7.53-7.45 (1H, m), 7.40-7.33 (2H, m), 5.26 (2H, m), 5.11 (1H, dt, J=3.0,48.0Hz), 4.46 (1H, dd, J=3.3,12.5Hz), 4.21 (1H, m), 3.94 (1H, dd, J=7.7,12.5Hz), 3.29 (1H, dd, J=3.3,7.7Hz), 2.44-1.44 (4H, m), 0.80 (9H, s), 0.01 (3H, s), 0.00 (3H, s).

Benzoic acid 2-[5-(tert-butyl group-dimethyl-silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethyl ester

With three (3,5-dimethyl pyrazole base) boron hydride rhenium trioxide (265mg, 0.50mmol), triphenylphosphine (158mg, 0.6mmol), benzoic acid (2R, 3S, 5S, 7R)-7-(tert-butyl group dimethyl) silanyloxy base)-5-fluoro-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester (203mg, 0.5mmol) and the mixture of toluene (8mL) in the argon lower seal ampoule, in 100 ℃ of heating 14 hours.(TLC, the 10%AcOEt solution in hexane, substrate and mixture of products, about 1: 1).Rhenium dioxide is all dissolvings not.(158mg, 0.6mmol) solution in toluene (4mL) and continuation heating are 6 hours to add triphenylphosphine.Reactant mixture is cooled to room temperature, filter through silicagel column, then with the residue behind the evaporating solvent through FC (20g, the solution of 5%AcOEt in hexane) purification obtains: title compound (120mg, 0.31mmol, the productive rate of required product is 61%) and the initiation material of 70mg add small amounts of contamination, about 34%.

(1Z, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol

To benzoic acid 2-[5-(tert-butyl group-dimethyl-silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-(150mg adds Feldalat NM (0.5mL, 15% methanol solution) to ethyl ester in methanol 0.38mmol) (3mL) solution.At room temperature stir and add entry (6mL) and (3 * 10mL) extract this mixture with dichloromethane after 1 hour.The organic layer Na that merges ₂SO ₄Drying also is evaporated to dried.Residue (0.2g) obtains title compound (80mg, 0.28mmol, 73% productive rate) through FC (20g, the 15%AcOEt solution in hexane) purification.

(1R, 3Z, 5S)-tert-butyl group-[3-(2-chloro-second subunit)-5-fluoro-4-methylene-cyclohexyl oxygen base]-dimethylsilane

Under 0 ℃ to (1Z, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol (8.07g, 28.2mmol) and triphosgene (4.18g, 14.1mmol) in the solution of hexane (150mL), go through and added pyridine (4.5mL in 30 minutes, 55.6mmol) solution in hexane (20mL), and this reactant mixture stirred 30 minutes under this temperature, then restir 30 minutes at room temperature.Use CuSO ₄(3 * 200mL) wash this reactant mixture to aqueous solution.(2 * 100mL) strip the water layer that merges with hexane.Organic layer is merged dry (MgSO ₄), and vacuum concentration obtains title compound (9.0g, overweight).This material need not be further purified and be used for next step immediately.[α] ²⁵ _D+73.0°(c 0.28，CHCl ₃)；IR(CHCl ₃)1643，838cm ^-1； ¹H-NMR δ0.08(s，6H)，0.88(s，9H)，1.84-2.03(m，1H)，2.12(br s，1H)，2.24(m，1H)，2.48(br d，J＝13Hz，1H)，4.06-4.26(m，3H)，5.10(br d，J＝48Hz)，5.16(s，1H)，5.35(s，1H)，5.63(br t，J＝6Hz，1H)。

(1S, 3Z, 5R)-1-fluoro-5-(tert-butyl group dimethyl) silanyloxy base)-2-methylene-3-(diphenylphosphine acyl group) second subunit cyclohexane extraction

(6.70g 33.1mmol) goes through and added NaH (1.33g, 33.1mmol, 60% dispersion liquid in mineral oil) in 15 minutes in batches in the suspension of DMF (50mL) with diphenyl phosphine oxide under 10 ℃.Gained solution at room temperature stirred 30 minutes and was cooled to-60 ℃.Dropwise add thick (1R, 3Z, 5S)-tert-butyl group-[3-(2-chloro-second subunit)-5-fluoro-4-methylene-cyclohexyl oxygen base]-solution of dimethylsilane (9.0g) in DMF (20mL).Reactant mixture was stirred 2 hours and at room temperature stirred 1 hour at-60 ℃, with ether (600mL) dilution and water (3 * 200mL) washings.Water layer extracts with ether (200mL).Dry (MgSO ₄) organic layer and the concentrating under reduced pressure that merge obtain white solid.Crude product is recrystallization in Di Iso Propyl Ether (25mL).Collect the gained solid by filtering,, obtain title compound (7.93g) with cold Di Iso Propyl Ether (5mL) washing and dry under fine vacuum.Concentrated mother liquor and with residue through silica gel chromatography (50g, the 30%-50%AcOEt solution in hexane) purification, obtain title compound (2.22g).Therefore (1S; 3Z; 5R)-1-fluoro-5-(tert-butyl group dimethyl) silanyloxy base)-total output of 2-methylene-3-(diphenylphosphine acyl group) second subunit cyclohexane extraction is (10.1g; 21.5mmol; with respect to (1Z; 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol is 76% gross production rate.[α] ²⁵ _D+ 50.2 ° (c 0.84, CHCl ₃); IR (CHCl ₃) 835,692cm ^-1UV λ _Max(ethanol) 223 (22770), 258 (1950), 265 (1750), 272nm (1280); MS, m/e 470 (M ⁺), 455 (4), 450 (8), 413 (98), 338 (9), 75 (100); ¹H-NMR: δ 0.02 (s, 6H), 0.84 (s, 9H), 1.76-1.93 (m, 1H), 2.16 (m, 2H), 2.42 (br d, 1H), 3.28 (m, 2H), 4.01 (m, 1H), 5.02 (dm, J=44Hz, 1H), 5.14 (s, 1H), 5.30 (s, 1H), 5.5 (m, 1H), 7.5 (m, 6H), 7.73 (m, 4H).C ₂₇H ₃₆O ₂The analytical calculation value of FPSi: C 68.91, and H 7.71, F4.04; Measured value: C 68.69, H 7.80, and F 3.88.

More extensive the synthesizing of A ring precursor

At room temperature to thick (S)-(Z)-2-[5-(tert-butyl group dimethyl) the silanyloxy base that stirred)-2-methylene-ring caproic subunit]-ethanol (13.5g, about 40mmol) in the solution of dichloromethane (100mL), adds AcONa (4.5g, 54.8mmol), then+5 ℃ add down 77% mCPBA (8.96g, 40.0mmol).At+5 ℃ this reactant mixture was stirred 1.5 hours, with hexane (500mL) dilution, water (200mL) and NaHCO ₃(2 * 200mL) washings, and use Na ₂SO ₄Dry.Residue behind the evaporating solvent (12.36g) need not be further purified and be directly used in next step. ¹H-NMR: δ 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J=5.6Hz), 3.60 (m, 2H), 3.86 (m, 1H), 4.91 (m, 1H).

At room temperature to the (2R that stirred, 3S, 7S)-[7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-yl]-methanol (12.36g) in the solution of pyridine (50mL), add Benzenecarbonyl chloride. (8.5mL, 73mmol) and stirred this reactant mixture 2 hours.Add entry (60mL) and also at room temperature stirred 45 minutes, use hexane (250mL) to dilute this mixture then, use NaHCO ₃Aqueous solution (2 * 250mL), saline (250mL) washs and uses Na ₂SO ₄Dry.Residue behind the evaporating solvent (15.28g) need not be further purified and be directly used in next step. ¹H NMR：δ8.04-7.80(2H，m)，7.56-7.50(1H，m)，7.44-7.37(2H，m)，4.94(1H，brs)，4.92(1H，brs)，4.32(1H，dd，J＝4.8，11.9Hz)，4.14(1H，dd，J＝6.2，11.9Hz)，3.83(1H，m)，3.21(1H，dd，J＝4.8，6.2Hz)，2.42(1H，m)，2.04-1.90(3H，m)，1.64-1.34(2H，m)，0.83(9H，s)，0.02(3H，s)，0.01(3H，s)。

Under 85 ℃ to the benzoic acid (2R that stirred, 3S, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester (adds selenium dioxide (4.26g in the solution of 15.28g) Zai diox (450mL), 38.4mmol), add tert-butyl hydroperoxide (7.7mL then, 38.4mmol, the solution of 5-6M in nonane), and reactant mixture stirred 13 hours down at 85 ℃, add selenium dioxide (2.39g, 21.5mmol), add tert-butyl hydroperoxide (4.3mL then, 21.5mmol, the solution of 5-6M in nonane) after, with reactant mixture 85 ℃ of following restir 24 hours.(0.5kg AcOEt) filters through silicagel column with this mixture.Solvent removed in vacuo also is dissolved in residue among the AcOEt (250mL), water (3 * 100mL) washings.Organic layer Na ₂SO ₄Dry also vacuum evaporation.Residue (16g) obtains: flow point A (1.1g, initiation material) through flash chromatography (0.5kg, 10,15 and the solution of 20%AcOEt in hexane) purification; Flow point B (0.78g, epimer b); Flow point C (3.01g, (epimer b: epimer was a) in 65: 35; Flow point D (6.22g, (epimer b: epimer was a) in 5: 95; With flow point D twice of crystallization (using remaining grease) from hexane at every turn, obtain pale yellow colored solid body portion E (6.0g altogether) and Huang-reddish oil part F (0.2g altogether).Flow point C and F obtain through flash chromatography (300g, the 20%AcOEt solution in hexane) purification: flow point G (0.8g, epimer b); (2.4g, 8: 92 epimer b: epimer a) for flow point H.With flow point H twice of crystallization (using remaining grease) from hexane at every turn, obtain pale yellow colored solid body portion I (2.2g altogether) and Huang-reddish oil part J (0.2g altogether).Flow point E and I merging are obtained epimer a (8.2g, 20.3mmol, 50.7% gross production rate).[α] ²² _D-10.6°(c 0.35，EtOH)； ¹HNMR：δ8.04(2H，m)，7.58(1H，m)，7.46(2H，m)，5.32(1H，br s)，5.18(1H，brs)，4.33(1H，dd，J＝5.2，11.9Hz)，4.21(1H，dd，J＝6.0，11.9Hz)，4.14(1H，ddd，J＝2.6，4.9，10.0Hz)，3.94(1H，m)，3.25(1H，dd，J＝5.5，5.9Hz)，2.38(1H，m)，2.05(1H，t，J＝11.5Hz)，1.64(1H，ddd，J＝1.9，4.3，12.2Hz)，1.52dt，J＝11.1，11.7Hz)，1.28(1H，m)，0.87(9H，s)，0.07(3H，s)，0.06(3H，s)；

¹³C NMR:166.31 (0), 145.52 (0), 133.29 (1), 129.65 (1), 129.54 (0), 128.46 (1), 107.44 (2), 68.51 (1), 65.95 (1), 62.75 (2), 61.62 (1), 61.09 (0), 45.23 (2), 44.33 (2), 25.72 (3), 18.06 (0) ,-4.72 (3); MS HR-ES: value of calculation C ₂₂H ₃₂O ₅Si:M+Na 427.1911 measured values: 427.1909.

Under-75 ℃ to the diethylamino sulfur trifluoride (16.5mL that stirred, 126.0mmol) in the solution of trichloroethylene (140mL), add benzoic acid (2R, 3S, 5R, 7S)-7-(tert-butyl group dimethyl) silanyloxy base)-5-hydroxyl-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester epimer a (18.7g, 46.2mmol) solution in trichloroethylene (100mL).After stirring 20 minutes under-75 ℃, add methanol (40mL), add NaHCO then ₃Aqueous solution (50mL) is also used hexane (700mL) dilution gained mixture, uses NaHCO ₃Na is used in aqueous solution (600mL) washing ₂SO ₄Dry and concentrated on Rotary Evaporators.Residue (25.6g) obtains title compound (13.9g, 34.2mmol, 74%) through flash chromatography (500g, DCM: hexane: AcOEt 10: 20: 0.2) purification; [α] ²⁹ _D+ 38.9 ° (c 0.8, CHCl ₃); ¹H NMR: δ 8.07 (2H, m), 7.57 (1H, m), 7.44 (2H, m), 5.33 (2H, m), 5.20 (1H, dt, J=2.9,48Hz), 4.55 (1H, dd, J=3.2,12.3Hz), 4.29 (1H, m), 4.02 (1H, dd, J=7.9,12.3Hz), 3.37 (1H, dd, J=3.2,7.7Hz), 2.45 (1H, m), 2.05 (1H, t, J=11.9Hz), 1.73 (1H, dm), 1.62 (1H, m), 0.88 (9H, s), 0.08 (3H, s), 0.06 (3H, s); ¹³C NMR:166.25 (0), 139.95 (0, d, J=17Hz), 132.97 (1), 129.75 (0), 129.62 (1), 128.24 (1), 116.32 (2, d, J=9Hz), 92.11 (1, d, J=162Hz), 65.23 (1), 63.78 (2), 62.29 (1), 60.35 (0), 44.38 (2), 41.26 (2, d, J=23Hz), 25.81 (3), 18.13 (0) ,-4.66 (3); MSHR-ES: value of calculation C ₂₂H ₃₁O ₄SiF:M+H 407.2049 measured values: 407.2046.

(1E, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol

(36.4g 91mmol) adds among the THF (800mL) with tungsten hexachloride at-75 ℃.Temperature is transferred to-65 ℃ and add n-BuLis (73mL, 182.5mmol, the 2.5M solution in hexane) down keeping temperature to be lower than-20 ℃.After adding reactant mixture is adjusted to room temperature and stirred 30 minutes, be cooled to 0 ℃, add benzoic acid (2R, 3S, 5S, 7R)-7-(tert-butyl group dimethyl) silanyloxy base)-5-fluoro-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester (18.5g, 45.5mmol) solution in THF (50mL).The mixture that forms is thus transferred to room temperature (2 hours) and stirred 16 hours.Add methanol (400mL), add Feldalat NM (250mL, 15% methanol solution) then, the gained mixture was stirred 30 minutes, use AcOEt (1L) dilution and water (1L) and saline (500mL) washing then.Dry (Na ₂SO ₄) the back evaporating solvent, residue (21.6g) need not be further purified and be directly used in next step.

¹H-NMR(CDCl ₃)；δ0.09(s，6H)，0.81(s，9H)，1.80-2.22(m，3H)，2.44(m，1H)，4.10(m，1H)，4.14(d，2H，J＝6.9Hz)，4.98(br s，1H)，5.10(d，1H，J＝50.0Hz)，5.11(s，1H)，5.79(t，1H，J＝6.8Hz)。

With (1E, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol (21.6g, the crude product that contains the 10%Z isomer) and the 9-Fluorenone (1.8g, 10mmol) solution in t-butyl methyl ether (650mL) is with 450W Hanovia (hanovia) light irradiation 8 hours that has uranium core filter.Residue behind the evaporating solvent (23.95g) is through purified by flash chromatography (750g, 5%, the solution of 20%AcOEt in hexane), obtain title compound (10.4g, 36.3mmol, press benzoic acid (2R, 3S, 5S, 7R)-7-(tert-butyl group dimethyl) silanyloxy base)-5-fluoro-4-methylene-1-oxa--spiral shell [2.5] suffering-2-ylmethyl ester meter, productive rate is 80%).[α] ³⁰ _D+40.1°(c 0.89，EtOH)

¹H-NMR：δ5.65(1H，t，J＝6.8Hz)，5.31(1H，dd，J＝1.5，1.7Hz)，5.10(1H，ddd，J＝3.2，6.0，49.9Hz)，4.95(1H，d，J＝1.7Hz)，4.28(1H，dd，J＝7.3，12.6Hz)，4.19(1H，ddd，J＝1.7，6.4，12.7Hz)，4.15(1H，m)，2.48(1H，dd，J＝3.8，13.0Hz)，2.27-2.13(2H，m)，1.88(1H，m)，0.87(9H，s)，0.07(6H，s)。 ¹³C-NMR：142.54(0，d，J＝17Hz)，137.12(0，d，J＝2.3Hz)，128.54(1)，115.30(2，d，J＝10Hz)，92.11(1，d，J＝168Hz)，66.82(1，d，J＝4.5Hz)，59.45(2)，45.15(2)，41.44(2，d，J＝21Hz)，25.76(3)，18.06(0)，-4.75(3)，-4.85(3)。

Under 0 ℃ to (1Z, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-ethanol (8.07g, 28.2mmol) and triphosgene (4.18g, 14.1mmol) in the solution of hexane (150mL), go through and added pyridine (4.5mL in 30 minutes, 55.6mmol) solution in hexane (20mL), and this reactant mixture stirred 30 minutes restir 30 minutes at room temperature then under this temperature.Use CuSO ₄(3 * 200mL) wash this reactant mixture to aqueous solution.(2 * 100mL) strip the water layer that merges with hexane.Merge organic layer, dry (MgSO ₄), vacuum concentration obtains title compound (9.0g, overweight).This material need not be further purified and promptly be used for next step.[α] ²⁵ _D+73.0°(c0.28，CHCl ₃)；IR(CHCl ₃)1643，838cm ^-1； ¹H-NMR δ0.08(s，6H)，0.88(s，9H)，1.84-2.03(m，1H)，2.12(br s，1H)，2.24(m，1H)，2.48(br d，J＝13Hz，1H)，4.06-4.26(m，3H)，5.10(br d，J＝48Hz)，5.16(s，1H)，5.35(s，1H)，5.63(br t，J＝6Hz，1H)。

Under 10 ℃, go through 15 minutes with diphenyl phosphine oxide (6.70g 33.1mmol) adds NaH (1.33g, 33.1mmol, 60% dispersion liquid in mineral oil) in the suspension of DMF (50mL) in batches.At room temperature stir gained solution 30 minutes and be cooled to-60 ℃.Dropwise add then thick (1R, 3Z, 5S)-tert-butyl group-[3-(2-chloro-second subunit)-5-fluoro-4-methylene-cyclohexyl oxygen base]-solution of dimethylsilane (9.0g) in DMF (20mL).This reactant mixture was stirred 2 hours and at room temperature stirred 1 hour at-60 ℃, dilute and wash (3 * 200mL) with water with ether (600mL).With ether (200mL) aqueous layer extracted.Dry (MgSO ₄) organic layer and the concentrating under reduced pressure that merge obtain white solid.With crude product recrystallization in Di Iso Propyl Ether (25mL).Collect the gained solid after filtration,, obtain title compound (7.93g) with cold Di Iso Propyl Ether (5mL) washing and dry under fine vacuum.Concentrated mother liquor and with residue through silica gel chromatography (50g, the 30%-50%AcOEt solution in hexane) purification, obtain title compound (2.22g).Therefore the total output of title compound be (10.1g, 21.5mmol, by (1Z, 3S, 5R)-2-[5-(tert-butyl group dimethyl) silanyloxy base)-3-fluoro-2-methylene-ring caproic subunit]-alcohol meter, gross production rate is 76%).[α] ²⁵ _D+ 50.2 ° (c 0.84, CHCl ₃); IR (CHCl ₃) 835,692cm ^-1UV λ _Max(ethanol) 223 (ε 22770), 258 (1950), 265 (1750), 272nm (1280); MS, m/e 470 (M ⁺), 455 (4), 450 (8), 413 (98), 338 (9), 75 (100); ¹H-NMR: δ 0.02 (s, 6H), 0.84 (s, 9H), 1.76-1.93 (m, 1H), 2.16 (m, 2H), 2.42 (br d, 1H), 3.28 (m, 2H), 4.01 (m, 1H), 5.02 (dm, J=44Hz, 1H), 5.14 (s, 1H), 5.30 (s, 1H), 5.5 (m, 1H), 7.5 (m, 6H), 7.73 (m, 4H).Analytical calculation value C ₂₇H ₃₆O ₂FPSi:C 68.91, H7.71; F 4.04; Measured value: C 68.69, H 7.80, and F 3.88.

C, D-ring/side chain precursor synthetic

(S)-2-((1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl)-propionic aldehyde

In the 250mL flask, pack into the Lythgoe glycol of 0.99g (4.67mmol), TEMPO, 146mg (0.53mmol) tetrabutylammonium chloride hydrate and the dichloromethane (50mL) of 75mg (0.48mmol).To be dissolved in the buffer for preparing in the 100mL volume water with sodium bicarbonate (4.2g) and potassium carbonate (0.69g) adds in the solution that this vigorous stirring crosses.This mixture of vigorous stirring also adds the N-chlorosuccinimide of 839mg (6.28mmol).TLC (1: 2, ethyl acetate-heptane) shows that chromatography thing (Rf 0.32) progressively is converted into the aldehyde (Rf 0.61) of title.The N-chlorosuccinimide that adds other 830mg (6.28mmol) after 18 hours added the TEMPO of 20mg, and stirred this mixture 24 hours after 1 hour.Separate organic layer and with dichloromethane (3 * 50mL) aqueous layer extracted again.With the organic extract that the salt water washing merges, dry and vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 3) and purification, obtain the thick aldehyde of 876mg (89%). ¹H NMR：δ9.58(1H，d，J＝2.8Hz)，4.12(1H，m)，2.50-2.30(1H，m)，2.10-1.10(13H，m)，1.11(3H，d，J＝7.0Hz)，0.99(3H，s)。

(1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-((S)-1-methyl-2-oxo-ethyl)-octahydro indenes-4-base ester

Will thick (S)-2-((1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl)-(255mg 1.21mmol) is dissolved in the pyridine (1mL) propionic aldehyde, this solution is cooled off in ice bath and adds DMAP (5mg) and acetic anhydride (0.5mL).At room temperature stir water (10mL) dilution after 24 hours of this mixture, stirred 10 minutes and used ethyl acetate (30mL) balance.The mixture of water (10mL) and 1N sulphuric acid (14mL) washs this organic layer, water (10mL) and saturated sodium bicarbonate solution (10mL) washing then, dry then and evaporation.Gained residue (201mg) ethyl acetate-hexane with 1: 4 on silicagel column carries out chromatographic isolation as mobile phase.Merge the flow point that comprises product, evaporation obtains title compound, is colourless syrup shape (169mg, 0.67mmol, 67%). ¹H NMR(300MHz，CDCl ₃)：δ9.56(1H，d，J＝2.0Hz)，5.20(1H，br s)，2.44-2.16(1H，m)，2.03(3H，s)，2.00-1.15(12H，m)，1.11(3H，d，J＝7.0Hz)，0.92(3H，s)。

Acetic acid (3aR, 4S, 7aR)-1-E-second subunit-7a-methyl-octahydro indenes-4-base ester

To (1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-((S)-1-methyl-2-oxo-ethyl)-octahydro indenes-4-base ester (480mg, 1.90mmol) palladium/carbon (25mg) of adding 10% in the solution of ether (5mL).This suspension was at room temperature stirred 20 minutes, through diatomite filtration and with the filtrate vacuum concentration.Palladium/the carbon (50mg) that in residue, adds benzalacetone (350mg, 2.40mmol distilled) and 10%.Suspension is by outgasing this flask evacuation, and feeds nitrogen again (2 *).Then this flask was immersed in 230 ℃ of heating baths 40 minutes.Dilute this suspension with ethyl acetate after being cooled to room temperature, through diatomite filtration and with the filtrate vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 9) and purification, obtain the mixture of the CD alkene of 290mg (68%).GC analyzes: title product (54%); Z isomer (4%); Internal olefin (27%); Terminal olefin (5%); Other impurity (10%).

(2R, 3aR, 4S, 7aR)-1-E-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (a) and acetic acid (2S, 3aR, 4S, 7aR)-1-E)-the basic ester (b) of second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-

To SeO ₂(460mg, 4.15mmol) in the suspension of dichloromethane (30mL), add the tert-butyl group-hydrogen peroxide (9.0mL, the 70w/w-% aqueous solution, 65.7mmol).At room temperature stirred this suspension 30 minutes, 0 ℃ of cooling, and in 30 minutes, dropwise add the CD-isomer (9.13g, 41.1mmol, comprise about 50% 16) solution in dichloromethane (35mL).Heat this reactant mixture to ambient temperature overnight and continue to stir 2 days at 30 ℃.Transform situation by gas chromatographic detection.By adding that entry comes quencher reaction and with dichloromethane (3 *) aqueous layer extracted.The organic layer that water (4 *) washing merges is used the salt water washing, dry (Na ₂SO ₄), filter and with the filtrate vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 3) and purification, obtain three main flow points: flow point 1: ketone (2.08g, 42% productive rate), by 2 kinds of contaminating impurities; Purity about 75%; Flow point 2: the mixing flow point (1.32g) of the unwanted isomer of pure epimer a+; Flow point 3: pure epimer a (2.10g, 42% productive rate); By-product contamination by about 12% is synthesized but purity is enough to carry out next step.Flow point 2 obtains the pure epimer a that 1.01g (20% productive rate) is polluted by about 20% unwanted isomer once more through the column chromatography purification, synthesizes but purity is enough to carry out next step. ^*Annotate: in the oxidation reaction that forms epimer a and two kinds of isomers of epimer b, observe by thin layer chromatography and gas chromatography.After prolonging the response time, the intensity of lower point (epimer b and other mixture of isomers) reduces and observes the formation of ketone on the thin layer chromatography.The important initiation material of being not only is converted into pure epimer a and epimer b fully, and is that epimer b is completely oxidized to ketone.Epimer b can not separate from unwanted isomer.The retention time of GC: initiation material retention time=8.06 minute; Product retention time=9.10 minute; Epimer b retention time=9.30 or 9.34 minutes; Ketone retention time=9.60 minute.Epimer a: ¹H NMR: δ 0.94 (s, 3H), 1.30 (m, 1H), 1.40-1.46 (m, 1H), 1.46-1.80 (m, 4H), 1.77 (dd, J=7.2,1.2Hz, 3H), 1.80-1.94 (m, 4H), 2.02 (s, 3H), 4.80 (br.s, 1H), 5.23 (m, 1H), 5.47 (qd, J=7.2,1.2Hz, 1H).GC-MS：m/e 223(M-15)，178(M-60)，163(M-75)。Epimer b: ¹H NMR: δ 1.24 (s, 3H), 1.38-1.60 (m, 5H), 1.68-1.88 (m, 3H), 1.72 (dd, J=7.2,1.2Hz, 3H), 1.99 (ddd, J=11.0,7.0,3.7Hz, 1H), 2.03 (s, 3H), 2.26 (m, 1H), 4.36 (m, 1H), 5.14 (m, 1H), 5.30 (qd, J=7.2,1.2Hz, 1H).GC-MS：m/e 223(M-15)，178(M-60)，163(M-75)。

Ketone is reduced into the epimer b of alcohol

With the solution of ketone (2.08g is by 2 kinds of contaminating impurities) in methanol (8mL) 0 ℃ the cooling and add in batches sodium borohydride (0.57g, 15.1mmol).After 1 hour, thin layer chromatography shows all conversions (thin layer chromatography does not have visible reactive compound under UV) 0 ℃ of stirring.By adding saturated NH ₄Cl aqueous solution (30mL) comes this reactant mixture of quencher.Add entry and use ethyl acetate (3 *) aqueous layer extracted.With the organic layer that the salt water washing merges, dry (Na ₂SO ₄), filter and with the filtrate vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 3) and purification, obtain the epimer b (1.20g, go through productive rate is 24% after two steps) of alcohol, be colorless oil.

Acetic acid (3aR, 4S, 7aR)-and 7a-methyl isophthalic acid-(1-(R)-methyl-3-oxo-propyl group)-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-base ester

With (2R, 3aR, 4S, 7aR)-1-E-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (a) and acetic acid (2S, 3aR, 4S, 7aR)-1-E)-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (b) (4.3g, 18.1mmol, purity 90%) is converted into chemical compound acetic acid (3aR in three batches, 4S, 7aR)-7a-methyl isophthalic acid-(1-(R)-methyl-3-oxo-propyl group)-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-base ester.(2.1g 8.82mmol) adds Hg (OAc) in the solution of ethyl vinyl ether (20mL) to epimer a ₂(2.23g, 7.00mmol).This suspension is poured in the heat resistant glass manometer tube, fed N ₂And sealing tightly.Stir this mixture 24 hours at 120 ℃, be cooled to room temperature and filtration.Vacuum concentrated filtrate also merges the crude product of residue and two other batches, through column chromatography (SiO ₂, ethyl acetate/heptane=1: 4) and purification twice, obtain title compound (2.58g, 60%), be light yellow oil.This product curing is stored in the refrigerator.Owing to have by-product in the initiation material, the column chromatography purification is favourable for the second time.

To isomer a and b (173mg, 0.73mmol) in the solution of toluene (2mL) [Ir (COD) Cl] of adding catalytic amount ₂(5mg), Na ₂CO ₃(46mg, 0.44mmol) and vinyl acetate (0.13mL, 1.45mmol).Heated this suspension 2 hours down at 100 ℃, thin layer chromatography shows that about 20% is converted into intermediate, (J.Am.Chem.Soc., 2002,134,1590-1591).Add more vinyl acetate (0.15mL) and continue stirring 18 hours at 100 ℃.Show the mixture that has formed intermediate and title compound according to thin layer chromatography, but initiation material does not transform fully yet.Add more vinyl acetate (2mL) and continue stirring 24 hours at 100 ℃.Thin layer chromatography shows that initiation material all is converted into intermediate and title compound.With this suspension vacuum concentration, with residue through column chromatography (SiO ₂, ethyl acetate/heptane=1: 9) and purification, obtain 60mg intermediate (31%) and 45mg title compound (23%). ¹H NMR：δ1.02(s，3H)，1.14(d，J＝7.1Hz，3H)，1.36(M，1H)，1.47-1.62(m，2H)，1.72-1.90(m，4H)，2.03(s，3H)，2.02-2.14(m，2H)，2.33(ddd，J＝16.2，7.3，2.6Hz，1H)，2.53(ddd，J＝16.2，5.8，1.8Hz，1H)，2.72(m，1H)，5.19(m，1H)，5.40(m，1H)，9.68(s，1H)。

5 (R)-((3aR, 4S, 7aR)-and 4-acetoxyl group-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl)-oneself-2-E-olefin(e) acid ethyl ester

At N ₂Under the gas with acetic acid (3aR, 4S, 7aR)-7a-methyl isophthalic acid-(1-(R)-methyl-3-oxo-propyl group)-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-base ester (2.24g, 8.47mmol) and phosphonoacetic acid triethyl (5.74g, 25.6mmol, 3 equivalents) and be dissolved in THF (40mL, fresh distillatory from the Na/ benzophenone).Cool off these mixture and in 20 minutes, dropwise add the solution of LiHMDS in hexane (16.8mL, 1M solution, 2 equivalents) at-100 ℃.

Stir after 70 minutes by dripping water (10mL) and adding saturated NH subsequently ₄Cl solution (10mL) comes the quencher reaction.Add entry and use t-butyl methyl ether (3 *) extraction.The organic layer that water (2 *), saline (1 *) washing merge, dry (Na ₂SO ₄), filter and with the filtrate vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 10) and purification, obtain title compound ester (2.15g, 76%), be water white oil; According to NMR purity:＞95% (not detecting the Z-isomer). ¹H NMR：δ0.99(s，3H)，1.06(d，J＝7.2Hz，3H)，1.27(t，J＝7.1Hz，3H)，1.36(td，J＝13.3，4.0Hz，1H)，1.46-1.62(m，2H)，1.72-1.90(m，4H)，1.96-2.17(m，3H)，2.03(s，3H)，2.22-2.39(m，2H)，4.17(q，J＝7.2Hz，2H)，5.20(br.s，1H)，5.37(br.s，1H)，5.78(dm，J＝15.4Hz，1H)，6.88(dt，J＝15.4，7.3Hz，1H)。HPLC: purity＞99% (218nm).HPLC-MS：m/e 357(M+23)，275(M-59)。

(3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol

With CeCl ₃* 7H ₂O (29.1g) is in 160 ℃ of vacuum (10 in three-neck flask ^-3Millibar) obtained anhydrous CeCl in dry 6 hours ₃(18.7g, 76.0mmol, 12 equivalents).At room temperature the cooling back feeds nitrogen in this flask.Add THF (200mL, fresh distillation from the Na/ benzophenone) and at room temperature stirred this mixture 18 hours.Cool off this suspension and in 20 minutes, dropwise add the solution of EtMgBr in THF (75mL, 1M solution) at 0 ℃ subsequently.Stir this light brown suspension at 0 ℃ and in 10 minutes, dropwise add 5 (R)-((3aR after 2 hours, 4S, 7aR)-4-acetoxyl group-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl)-and oneself-2-E-olefin(e) acid ethyl ester (2.15g, 6.42mmol) solution in THF (30mL, fresh distillation from the Na/ benzophenone).0 ℃ stir 30 minutes after thin layer chromatography show and transform fully, come the quencher reaction by adding entry (60mL).Add more water also with the solution extraction (3 *) of 50% ethyl acetate in heptane.Use saturated NaHCO ₃The organic layer that solution (2 *), saline (1 *) washing merge, dry (Na ₂SO ₄), filter and the filtrate vacuum concentration is obtained light yellow oil.With this crude product (2.4g) with second batch (available from the 600mg of 550mg initiation material thick (3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol) merges.Through column chromatography (SiO ₂, ethyl acetate/heptane=1: 3) purification obtain (3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (2.45g, 99%) are water white oil. ¹H NMR：δ0.84(t，J＝7.3Hz，6H)，1.04(d，J＝7.2Hz，3H)，1.05(s，3H)，1.23-1.60(m，9H)，1.67-2.02(m，6H)，2.12-2.32(m，3H)，4.17(m，1H)，5.33(m，1H)，5.35(dm，J＝15.4Hz，1H)，5.51(ddd，J＝15.4，7.4，6.5Hz，1H)。HPLC: purity=98% (212nm).HPLC-MS：m/e 330(M+24)，289(M-17)，271(M-35)。

(3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone

Will (3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (465mg, 1.52mmol) solution in dichloromethane (30mL) cools off in ice bath, and with pyridinium dichromate (1.28g, 3.40mmol, 2.2 equivalents) handle in batches.This reactant mixture was stirred 6 hours and at room temperature stirred 18 hours at 0 ℃.With this reactant mixture through diatomite filtration.With the washed with dichloromethane filter cake and with the filtrate vacuum concentration that merges.Residue is through column chromatography (SiO ₂, the solution of 25% ethyl acetate in heptane) and purification obtains title compound (320mg, 69%), is water white oil. ¹H NMR：δ0.82(s，3H)，0.85(br.t，J＝7.2Hz，6H)，1.05(d，J＝6.9Hz，3H)，1.34(br.s，1H)，1.52(br.q，J＝6.9Hz，4H)，1.65(td，J＝12.1，5.6Hz，1H)，1.84-1.93(m，1H)，1.93-2.16(m，4H)，2.16-2.33(m，4H)，2.42(ddt，J＝15.4，10.4，1.6Hz，1H)，2.82(dd，J＝10.4，6.0Hz，1H)，5.30(m，1H)，5.38(dm，J＝15.6Hz，1H)，5.54(ddd，J＝15.6，7.1，6.0Hz，1H)。

More massive C, D-ring/side chain precursor synthetic

Acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxy propane-2-yl)-7a-methyl-octahydro-1H-indenes-4-base ester

In 1 liter of round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into Lythgoe glycol initiation material (38.41g, 180.9mmol), dichloromethane (400mL), pyridine (130mL) and DMAP (5.00g, 40.9mmol).Slowly add acetic anhydride (150mL) and at room temperature stirred this mixture 14.5 hours.Dropwise add methanol (70mL) in (exothermic reaction) this reactant mixture and stirred this solution 30 minutes.Add entry (1L) and use dichloromethane (2 * 250mL) aqueous layer extracted.HCl (200mL) and NaHCO with 1N ₃Solution (200mL) washing extract, dry (Na ₂SO ₄) and be evaporated to dried with toluene (150mL).Be dissolved in residue in the methanol (300mL) and add sodium carbonate (40.0g).Stirred this suspension 24 hours.Add other a part of sodium carbonate (10.0g), stirred this reactant mixture 18 hours.On Rotary Evaporators, remove methanol.Also (3 * 250mL) extract this mixture, dry (Na with ethyl acetate to add entry (500mL) ₂SO ₄) and vacuum concentration.Residue through FC (0.4kg silica gel, 20%, 30% hexane-ethyl acetate) purification obtain title compound acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxy propane-2-yl)-7a-methyl-octahydro-1H-indenes-4-base ester (45g, 98%). ¹HNMR(DMSO-D6)5.03(1H，br s)，4.26(1H，dd，J＝5.9，5.1Hz)，3.42-3.36(1H，m)，3.10-3.02(1H，m)，1.99(3H，s)，1.96-1.91(1H，m)，1.77-1.58(3H，m)，1.50-1.08(9H，m)，0.93(3H，d，J＝6.6Hz)，0.85(3H，s)。

Acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-((S)-oxo propane-2-yl)-octahydro-1H-indenes-4-base ester

(17mL, (27mL, the 380mmol) solution in dichloromethane (200mL) keep temperature to be lower than-65 ℃ 195mmol) to add DMSO in the solution of dichloromethane (150mL) to refrigerative (65 ℃) oxalyl chloride in 35 minutes.Adding the back continues to stir 15 minutes at-65 ℃.In 80 minutes, dropwise add then acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxy propane-2-yl)-7a-methyl-octahydro-1H-indenes-(41g, the 161mmol) solution in dichloromethane (300mL) keep temperature to be lower than-65 ℃ to 4-base ester.Solid precipitation in the dropping process.Adding the back continues to stir 1 hour at-65 ℃.In 30 minutes, dropwise add the solution of triethylamine (110mL) in dichloromethane (200mL) then.Adding the back continues to stir 45 minutes at-65 ℃.Remove cooling bath and in 1 hour, reactant mixture is heated to 5 ℃.Remove dichloromethane (about 600mL) and in residue, add entry (600mL) and the tert-butyl group-methyl ether (500mL) by distilling under reduced pressure.Separate organic layer and use the tert-butyl group-methyl ether (2 * 200mL) aqueous layer extracted.Dry (Na ₂SO ₄) organic layer that merges, filter and vacuum concentration.Residue obtains 38g (94%) title compound through column chromatography (800g silica gel, the solution of 15% ethyl acetate in heptane) purification, is light yellow oil. ¹H NMR(CDCl ₃)：δ9.56(1H，d，J＝2.0Hz)，5.20(1H，br s)，2.44-2.16(1H，m)，2.03(3H，s)，2.00-1.15(12H，m)，1.11(3H，d，J＝7.0Hz)，0.92(3H，s)。

Benzalacetone process ball-ball distillation before use (130 ℃, 10 ^-2Millibar) purification.To acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-((S)-oxo propane-2-yl)-octahydro-1H-indenes-(38.3g 0.15mol) adds palladium/carbon (1.8g) of 10% to 4-base ester in the solution of ether (240mL).At room temperature stirred this suspension 45 minutes, through diatomite filtration and with the filtrate vacuum concentration.(28.3g is 0.19mol) with 10% palladium/carbon (1.8g) to add benzalacetone in residue.By the flask evacuation being made this suspension degassing and feeding nitrogen again.Then this flask is partly immersed in 230 ℃ of oil baths and continue 40 minutes.Dilute this suspension with ethyl acetate after being cooled to room temperature, through diatomite filtration and with the filtrate vacuum concentration.Residue is through the column chromatography (SiO of 1800g ₂, the solution of 5-10% ethyl acetate in heptane) and purification, obtain the Δ of 21.6g (65%) ^17E, Δ ^17Z, Δ ¹⁶And Δ ²⁰There is (GC analysis) in the mixture of indenes alkene with 51%, 4%, 25% and 1% concentration respectively.This isomer mixture need not be further purified and be directly used in next step.

¹H NMR (CDCl ₃, required Δ ^17EThe signal of isomer): 5.21 (m, 1H), 4.98-5.07 (m, 1H), 2.15-2.35 (m, 2H), 2.05 (s, 3H), 1.53 (d, 3H, J=7Hz), δ 0.96 (s, 3H).

In different experiments, press chromatography from alkene mixture (Δ in the silica gel that required product is handled by silver nitrate ^17E: Δ ^17Z: Δ ¹⁶: Δ ²⁰=65: 4: 27: 4) separate in, productive rate is 55% (U.S. Patent number 5,939,408).

(2R, 3aR, 4S, 7aR)-1-E-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (17a) and acetic acid (2S, 3aR, 4S, 7aR)-1-E)-the basic ester of second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-

To SeO ₂(1.4g; 12.6mmol) in the solution of dichloromethane (55mL), add tert-butyl hydroperoxide (17mL, the 70w/w-% aqueous solution, 124mmol).At room temperature stirred this suspension 30 minutes, 0 ℃ of cooling and dropwise add acetic acid (3aR, 4S, 7aS, E)-1-second subunit-7a-methyl-octahydro-1H-indenes-(it is a Δ to 4-base ester for 18.8g, 84.5mmol ^17E, Δ ^17Z, Δ ¹⁶And Δ ²⁰The part of indenes alkene mixture; Comprise 51% required isomer, promptly acetic acid (3aR, 4S, 7aR)-1-E-second subunit-7a-methyl-octahydro indenes-4-base ester) solution in dichloromethane (70mL).Stirred this reactant mixture 1 hour at 0 ℃, at room temperature stirred 18 hours and stirred 3 days at 30 ℃ subsequently.In this reactant mixture, add entry (350mL) and ethyl acetate (400mL).Use ethyl acetate (1 * 400mL, 1 * 350mL, 1 * 150mL) aqueous layer extracted after the layering.To fully mix each layer 60 minutes in the organic moiety of water (600mL) adding merging and by magnetic agitation.Separate organic layer, dry (Na ₂SO ₄) and vacuum concentration.Residue is through column chromatography (1kg SiO ₂Solution, 25%AcOEt the solution in heptane of 4L, 33%AcOEt the eluant solution in heptane of 4L of 20%AcOEt in heptane with 4L) purification obtains: flow point A (4.2g comprises the segmental mixture of about 75% ketone); Flow point B (7.2g alcohol acetic acid (3aR, 4S, 7aR)-and 1-E-second subunit-7a-methyl-octahydro indenes-4-base ester, purity about 90%).Flow point A is dissolved in methanol (100mL) and 0 ℃ of cooling.Add in batches sodium borohydride (1.1g, 29mmol).After 40 minutes, thin layer chromatography shows that conversion fully 0 ℃ of stirring.By adding saturated NH ₄Cl aqueous solution (30mL) comes this reactant mixture of quencher, and extracts with ethyl acetate (3 *).With the organic layer that the salt water washing merges, dry (Na ₂SO ₄), filter and with the filtrate vacuum concentration.Residue (4.5g) is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 3) and purification obtains: flow point C (3.2g, pure acetic acid (2S, 3aR, 4S, 7aR)-1-E)-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (b)).Flow point B and C merging are obtained 10.4g alcohol (2R, 3aR, 4S, 7aR)-1-E-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (a) and acetic acid (2S, 3aR, 4S, 7aR)-1-E)-second subunit-2-hydroxyl-7a-methyl-octahydro indenes-4-base ester (b) is (by 51% initiation material amount in the CD alkene mixture, productive rate is 93%) mixture, be water white oil.

Alcohol a: ¹H NMR (CDCl ₃): δ 5.47 (qd, J=7.2,1.2Hz, 1H), 4.80 (br.s, 1H), 5.23 (m, 1H), 1.80-1.94 (m, 4H), 2.02 (s, 3H), 1.77 (dd, J=7.2,1.2Hz, 3H), 1.46-1.80 (m, 4H), 1.40-1.46 (m, 1H), 1.30 (m, 1H), 0.94 (s, 3H); GC-MS:m/e223 (M-15), 178 (M-60), 163 (M-75); MS:m/e 223 (M-15), 178 (M-60), 163 (M-75).

Alcohol b: ¹H NMR (CDCl ₃): δ 5.30 (qd, J=7.2,1.2Hz, 1H), 5.14 (m, 1H), 4.36 (m, 1H), 2.26 (m, 1H), 2.03 (s, 3H), 1.99 (ddd, J=11.0,7.0,3.7Hz, 1H), 1.72 (dd, J=7.2,1.2Hz, 3H), and 1.68-1.88 (m, 3H), 1.38-1.60 (m, 5H), 1.24 (s, 3H); GC-MS:m/e 223 (M-15), 178 (M-60), 163 (M-75); MS:m/e 223 (M-15), 178 (M-60), 163 (M-75).

With acetic acid (2R, 3aR, 4S, 7aR, Z)-1-second subunit-2-hydroxyl-7a-methyl-octahydro-1H-indenes-4-base ester and acetic acid (2S, 3aR, 4S, 7aS, Z)-1-second subunit-2-hydroxyl-7a-methyl-octahydro-1H-indenes-(12.5g, mixture 47mmol) are dissolved in the ethyl vinyl ether (150mL) 4-base ester.Add Hg (OAc) ₂(14.1g 44mmol) also pours this suspension in the heat resistant glass manometer tube into, charges into N ₂And tightly sealing.Stirred this mixture 18 hours at 130 ℃, at room temperature cooling and vacuum concentration.Residue is through column chromatography (SiO ₂, the solution of the ethyl acetate of 7.5-30% in heptane) and purification obtains: flow point A (8.1g (65%) title compound); Flow point B (1.8g comprises the mixture of about 50% title compound).Flow point B is through column chromatography purification (SiO ₂, the solution of 7.5-30% ethyl acetate in heptane) obtain: flow point C (0.6g title compound).Flow point A and C merging are obtained 8.7g (70%) title compound, be water white oil. ¹H NMR(CDCl ₃)：δ9.68(s，1H)，5.40(m，1H)，5.19(m，1H)，2.72(m，1H)，2.53(ddd，J＝16.2，5.8，1.8Hz，1H)，2.33(ddd，J＝16.2，7.3，2.6Hz，1H)，2.03(s，3H)，2.02-2.14(m，2H)，1.72-1.90(m，4H)，1.47-1.62(m，2H)，1.36(M，1H)，1.14(d，J＝7.1Hz，3H)，1.02(s，3H)。

With acetic acid (3aR, 4S, 7aS)-7a-methyl isophthalic acid-((S)-4-oxo-butanes-2-yl)-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-base ester (16.2g; 61mmol) with phosphonoacetic acid triethyl (36mL; 183mmol, 3 equivalents) at N ₂Be dissolved in THF (200mL, fresh distillation from the Na/ benzophenone) in the gas.This mixture is cooled to-90 ℃ and dropwise added the solution of LiHMDS in hexane (122mL, 1M solution, 2 equivalents) in 45 minutes, keeps temperature to be lower than-90 ℃.After adding this reactant mixture heated to-78 ℃ and under this temperature, continue to stir 70 minutes.By dropwise adding entry (64mL) and saturated NH ₄The mixture of Cl solution (32mL) comes this reaction of quencher.In this reactant mixture, add t-butyl methyl ether (400mL) and water (400mL), separate organic layer and concentrating under reduced pressure and obtain flow point A.Water layer is through t-butyl methyl ether (1 * 400mL, 1 * 200mL) extraction.Organic layer and flow point A are merged, and (2 * 200mL) washings are with saline (1 * 150mL) washing, dry (Na for water ₂SO ₄), filter and with the filtrate vacuum concentration.Residue is through column chromatography (SiO ₂, ethyl acetate/heptane=1: 10) and purification obtains title compound (18g, 88%), is E/Z-mixture (E: Z=10: 1). ¹H NMR(CDCl ₃)：δ6.88(dt，J＝15.4，7.3Hz，1H)，5.78(dm，J＝15.4Hz，1H)，5.37(br.s，1H)，5.20(br.s，1H)，4.17(q，J＝7.2Hz，2H)，2.03(s，3H)，2.22-2.39(m，2H)，1.96-2.17(m，3H)，1.72-1.90(m，4H)，1.46-1.62(m，2H)，1.36(td，J＝13.3，4.0Hz，1H)，1.27(t，J＝7.1Hz，3H)，1.06(d，J＝7.2Hz，3H)，0.99(s，3H)；MS：m/e 357(M+23)，275(M-59)。

Cerium chloride (III) heptahydrate of in a 1L round-bottomed flask, packing into (234g, 0.63mol), in a vacuum (10-2 millibar) through the distillation of ball-ball respectively in 70 ℃ (30 minutes), 95 ℃ (3 hours), 120 ℃ (1 hour) and 160 ℃ (3 hours) slowly heating come except that anhydrating (about 70g).After the cool overnight canescence cerium chloride (III) monohydrate (162g) at room temperature is transferred in a vacuum in the three-neck flask of a 3L that magnetic stirring bar is installed.By stirring and in a vacuum (10 ^-2Millibar) respectively at 90 ℃ (1 hours), 120 ℃ (1 hour), 160 ℃ (1 hour) and 210 ℃ (4 hours) adds last normal water of heat extraction.The condensed water at flask top is by adding heat extraction with hot rifle (hot gun).When no longer observing condensed water formation, water is removed and is finished.This flask is cooled off and feeding nitrogen in room temperature.Add THF (1.3L) and at room temperature stirred this mixture 18 hours.This emulsus suspension is cooled off and dropwise added the solution of EtMgBr in THF (610mL, 1M solution) at 0 ℃ in 1 hour.In 1 hour, dropwise add (S after 2 hours 0 ℃ of stirring, E)-5-((3aR, 4S, 7aS)-4-acetoxyl group-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl)-hexenoic acid ethyl ester (16.2g, 48.4mmol the corresponding Z by about 10%-isomer is polluted) solution in THF (75mL).0 ℃ stir 1 hour after thin layer chromatography show to transform fully and and come this reaction of quencher by slowly adding entry (150mL, exothermic reaction), precipitate until viscous solid.Pour out this solution (flow point A) and residual solid and water (1L) fully mixed and obtain aqueous suspension (flow point B).Flow point A and B merged and with the mixture extraction of ethyl acetate (500mL) and heptane (500mL) four times.Use saturated NaHCO ₃The organic layer that solution (2 *), saline (1 *) washing merge, dry (Na ₂SO ₄), filter and with the filtrate vacuum concentration.Residue (17g) is through the column chromatography (SiO of 1kg ₂, the solution of 20% ethyl acetate in heptane) and purification obtains title compound (13.4g, 98%), is light yellow oil.Purity according to HPLC: 93.1% (λ=212nm).Product is through the column chromatography (SiO of 1kg ₂, the solution of 20% ethyl acetate in heptane) once more purification obtain: flow point A, 11.91g (86% productive rate) title compound is water white oil; Purity according to HPLC:＞96.5% (λ=212nm); Flow point B, 1.40g (10% productive rate) title compound is water white oil; Purity according to HPLC: 86.9% (λ=212nm); ¹H NMR (CDCl ₃): δ 5.51 (ddd, J=15.4,7.4,6.5Hz, 1H), 5.35 (dm, J=15.4Hz, 1H), 5.33 (m, 1H), 4.17 (m, 1H), 2.12-2.32 (m, 3H), 1.67-2.02 (m, 6H), 1.23-1.60 (m, 9H), 1.05 (s, 3H), 1.04 (d, J=7.2Hz, 3H), 0.84 (t, J=7.3Hz, 6H); MS:m/e 329 (M+23), 289 (M-17), 271 (M-35).

Will (3aR, 4S, 7aS)-1-((S, E)-6-ethyl-6-hydroxyl suffering-4-alkene-2-yl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (4.70g, 15.3mmol, purity according to HPLC: 96.5% (λ=212nm) solution in dichloromethane (200mL) cools off in ice bath, dropwise adding pyridinium dichromate (13.1g, 34.9mmol, 2.2 equivalents) handles.This reactant mixture is heated to ambient temperature overnight, also use the washed with dichloromethane filter cake through diatomite filtration.KHCO with 2M ₃The filtrate that solution washing merges is used the salt water washing, dry (Na ₂SO ₄) and vacuum concentration.Residue is through column chromatography (SiO ₂, the solution of 25% ethyl acetate in heptane) and purification obtains title compound (4.0g, 85%), is water white oil.

¹H NMR(CDCl ₃)：δ5.54(ddd，J＝15.6，7.1，6.0Hz，1H)，5.38(dm，J＝15.6Hz，1H)，5.30(m，1H)，2.82(dd，J＝10.4，6.0Hz，1H)，2.42(ddt，J＝15.4，10.4，1.6Hz，1H)，2.16-2.33(m，4H)，1.93-2.16(m，4H)，1.84-1.93(m，1H)，1.65(td，J＝12.1，5.6Hz，1H)，1.52(br.q，J＝6.9Hz，4H)，1.34(br.s，1H)，1.05(d，J＝6.9Hz，3H)，0.85(br.t，J＝7.2Hz，6H)，0.82(s，3H)。

Coupling is with synthetic

1-(5-ethyl-1-methyl-5-TMS oxygen base-heptan-3-thiazolinyl)-7a-methyl-3,3a, 5,6,7,7a-six hydrogen-indenes-4-ketone

To (3aR, 4S, 7aR)-1-((S, E)-5-ethyl-5-hydroxyl-1-methyl-heptan-3-thiazolinyl)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (320mg, 1.05mmol) in the solution of dichloromethane (20mL), add 1-(TMS) imidazoles (0.2mL, 1.34mmol).At room temperature stirred this reactant mixture 4 days.Reaction control (thin layer chromatography) shows that conversion fully.With this mixture vacuum concentration and with residue through column chromatography (SiO ₂, the solution of 10% ethyl acetate in heptane) and purification obtains title compound (377mg, 95%), is water white oil.

1 α-fluoro-25-hydroxyl-16-23E-diene-26,27-pair of high-20-table-cholecalciferol

-78 ℃, in argon to the (1S of the 240mg that stirred (0.51mmol); 3Z, 5R)-1-fluoro-5-(tert-butyl group dimethyl) silanyloxy base)-2-methylene-3-(diphenylphosphine acyl group) second subunit cyclohexane extraction dropwise adds the solution of 1.6M n-BuLi in hexane of 0.319mL (0.51mmol) in the solution of 5mL anhydrous tetrahydro furan.Stir after 5 minutes, in 10 minutes, in the gained red solution, dropwise add 1-(5-ethyl-1-methyl-5-TMS oxygen base-heptan-3-thiazolinyl)-7a-methyl-3 of 103mg (0.273mmol), 3a, 5,6,7, the 7a-six hydrogen-indenes-solution of 4-ketone in the 4mL anhydrous tetrahydro furan.This reactant mixture was stirred 2 hours at-78 ℃, placed refrigerator (20 ℃) then one hour, come the quencher reaction by 2N Rochelle salt and 1: 1 mixture of 2N potassium bicarbonate that adds 10mL, and heat to room temperature.After this salt mixture dilution of other 25mL, with 3 * 90mL ethyl acetate extraction.The organic layer that water and salt water washing merge three times is through dried over sodium sulfate and be evaporated to dried.Residue " with hexane-ethyl acetate (1: 4) purification, obtains the title compound of 145mg disilane baseization on the silicagel column through flash chromatography in 30mm * 7.The solution of 1M tetrabutylammonium in oxolane that in argon, in the solution of 3mL anhydrous tetrahydro furan, adds 1.7mL (1.7mmol) to 145mg disilane base intermediate.At room temperature stirred this reactant mixture 18 hours, then by adding 10mL water and stirring and came the quencher reaction in 15 minutes.With the dilution of 20mL water and saline and with 3 * 80mL ethyl acetate extraction.Organic layer water and salt water washing four times through dried over sodium sulfate, and are evaporated to dried.Crude product " is used hexane-ethyl acetate (3: 2) purification, and is used hexane-ethyl acetate (1: 1) purification by HPLC on YMC 50mm * 50cm silicagel column in 30mm * 5 through flash chromatography on the silicagel column.Obtain 90mg (74%) title compound, crystallization from methyl acetate-hexane.

More massive coupling is with synthetic

To (3aR, 7aS)-1-((S, E)-6-ethyl-6-hydroxyl suffering-4-alkene-2-yl)-7a-methyl-3,3a, 5,6,7,7a-six hydrogen-3H-indenes-4-ketone (4.0g, 13.1mmol) in the solution of dichloromethane (200mL), add 1-(TMS) imidazoles (2.2mL, 14.9mmol).At room temperature stirred this reactant mixture 18 hours.Because thin layer chromatography shows unconverted complete, (4.3mL 29.1mmol) also continues to stir 5 hours to add 1-(TMS) imidazoles again.With this mixture 30 ℃ of concentrating under reduced pressure and with residue through the column chromatography (SiO of 200g ₂, the solution of 10% ethyl acetate in heptane) and purification obtains title compound (4.6g, 93%), is water white oil.Purity according to HPLC: 100% (λ=265nm); ¹H NMR (CDCl ₃): δ 5.28-5.52 (m, 3H), 2.83 (dd, J=10.4,6.1Hz, 1H), 2.43 (ddm, J=15.4,10.4Hz, 1H), 2.18-2.32 (m, 4H), 1.94-2.18 (m, 4H), 1.85-1.93 (m, 1H), 1.76 (td, J=12.4,5.6Hz, 1H), 1.53 (br.q, J=7.3Hz, 4H), 1.16 (d, J=6.9Hz, 3H), 0.83 (s, 3H), 0.81 (br.t, J=7.1Hz, 6H), 0.47 (s, 9H); MS:m/e 376 (M), 361 (M-15), 347 (M-29).

In a 25mL flask, pack into (1S, 3Z, 5R)-1-fluoro-5-(tert-butyl group dimethyl) silanyloxy base)-2-methylene-3-(diphenylphosphine acyl group) second subunit cyclohexane extraction (748mg; 1.59mmol; 1.2 equivalent) and (3aR, 7aS)-1-((S, E)-6-ethyl-6-(TMS oxygen base) suffering-4-alkene-2-yl)-7a-methyl-3; 3a; 5,6,7; 7a-six hydrogen-3H-indenes-4-ketone (499mg, 1.32mmol).(3 * 5mL) steam altogether, are dissolved among the THF (10mL, fresh distillation from the Na/ benzophenone) and are cooled to-55 ℃ with this mixture and toluene.In 5 minutes, dropwise add LiHMDS (1.65mL, the 1M solution in THF, 1.2 equivalents).This dark red solution was heated to-25 ℃ in 1.5 hours.Adding TBAF (9mL, the THF solution of 1M) (color becomes orange) also heats this mixture to ambient temperature overnight.By slowly pouring the KHCO of ice-cooled 1M into ₃Aqueous solution comes this reaction of quencher.With the ethyl acetate (mixture that 3 * 25mL) extractions form thus.The organic layer that water, saline (3 *) washing merge, dry (Na ₂SO ₄) and at 30 ℃ of vacuum concentration.Residue is through column chromatography purification (solution of 25% ethyl acetate in heptane), obtain: the CD-construction unit of the epimerization of flow point A:35mg (7%), i.e. table-(3aR, 7aS)-1-((S, E)-6-ethyl-6-(TMS oxygen base) suffering-4-alkene-2-yl)-7a-methyl-3,3a, 5,6,7,7a-six hydrogen-3H-indenes-4-ketone.Flow point B: the vitamin D of trace-relevant by-product.The title compound of flow point C:27mg (5%) is white solid; Purity according to HPLC: 96.8% (λ=265nm).Flow point D:450mg (75%) title compound is white solid; Purity according to HPLC: 93.7% (λ=265nm).Flow point E:30mg (5%) title compound is white solid; Purity according to HPLC: 92.9% (λ=265nm).Flow point D is dissolved in the methyl formate (3-4mL).Add heptane (15mL) and in flask, feed nitrogen until the solution becomes muddiness.Product begins crystallization, and this flask is stored 1 hour so that crystallization is complete at 4 ℃.Pour out solvent also with cold heptane (the remaining solid of 3 * 5mL) washings.With this solid vacuum drying, obtain: flow point F:331mg (56% productive rate) title compound is white solid behind the feeding nitrogen; Purity according to HPLC: 100% (λ=265nm); ¹H NMR (CD ₃CN): δ 6.42 (br d, 1H), 6.10 (br d, 1H), 5.51 (ddd, 1H), 5.39 (brd, 1H), 5.36 (br s, 1H), 5.35 (br d, 1H), 5.13 (ddd, 1H), 5.07 (br s, 1H), 3.97-4.05 (m, 1H), 2.92 (d, 1H), 2.85 (dd, 1H), 2.57 (dd, 1H), 2.38 (dd, 1H), and 2.14-2.29 (m, 5H), 1.96-2.04 (m, 2H), 1.84-1.89 (m, 1H), 1.73-1.82 (m, 3H), 1.64-1.72 (m, 1H), 1.53 (ddd, 1H), 1.45 (br.q, 4H), 1.04 (d, 3H), 0.81 (t, 6H), 0.69 (s, 3H); ¹³C NMR (CD ₃CN): 160.12,143.37 (d, J=17Hz), 142.83,137.33,133.21 (d, J=2Hz), 126.96,124.84,120.83,117.33 (d, J=32Hz), 115.40 (d, J=10Hz), 93.74,91.51,74.83,65.72 (d, J=5Hz), 58.19,50.31,45.14,40.94 (d, J=21Hz), 39.78,35.21,33.34,33.33,32.46,29.33,28.63,23.56,20.33,16.74,1.41. ¹⁹F NMR(CD ₃CN)：δ-177.55；MS：m/e 482(M+39)，465(M+23)，425(M-17)。UVλmax：244nm(ε13747)，270nm(ε13756)(CH ₃OH)。[α] ^D ₂₅+101(c 1.92，CH ₃OH)。

Alternative coupling is with synthetic

With 1S; 3Z; 5R)-1-fluoro-5-(tert-butyl group dimethyl) silanyloxy base)-2-methylene-3-(diphenylphosphine acyl group) second subunit cyclohexane extraction (278mg; 0.59mmol; 3.6 equivalent) solution in THF (10mL distills from the Na-benzophenone) is-75 ℃ of coolings, and dropwise adds n-BuLi (0.23mL; 2.5M the solution in hexane, 0.57mmol).Stirred this red solution 20 minutes, temperature rises to-50 ℃ in this process.In 5 minutes, under-50 ℃, dropwise add (3aR, 7aS)-1-((S, E)-6-ethyl-6-hydroxyl suffering-4-alkene-2-yl)-7a-methyl-3,3a, 5,6,7,7a-six hydrogen-3H-indenes-4-ketone (50mg, 0.164mmol) solution in THF (2mL distills in the Na-benzophenone).Continue to stir 2 hours, temperature rises to-10 ℃ in this process.Thin layer chromatography shows that about 20% transforms.Dropwise add TBAF (1.8mL, the THF solution of 1M comprises about 5% water) in this yellow solution, this solution becomes brownish red subsequently.This reactant mixture is heated to ambient temperature overnight.By adding the KHCO of ice-cooled 1M ₃Aqueous solution (3g in 30mL water) comes this reactant mixture of quencher, and (2 * 40mL) extract this mixture with ethyl acetate.The organic layer that water and salt water washing merge, dry (Na ₂SO ₄), filter and with filtrate at 30 ℃ of vacuum concentration.Residue is through column chromatography (SiO ₂, the solution of 25% ethyl acetate in heptane) and purification obtains title compound (13mg, 18%), is the white foam shape.

Embodiment 2

21-(3-hydroxy-3-methyl butyl)-1,25-dihydroxy-19-fall-cholecalciferol synthetic

[1R-[1 α (2E, 4E, 7E), 3a β, 4 α, 7a α]]-5-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl]-2,4,7-enedioic acid diethylester in the ninth of the ten Heavenly Stems three

[1R-(1 α to the 3.08g that stirred (10.0mmol), 3a β, 4 α, 7a α)]-(1, the 1-dimethyl ethyl) dimethyl [[octahydro-7a-methyl isophthalic acid-(1-methyl ethylene)-1H-indenes-4-yl] oxygen base] silane and 3.92g (40.0mmol) ethyl propiolate add the solution of 40mL (40.0mmol) 1.0M ethylaluminum dichloride in hexane in the solution of 20mL dichloromethane.At room temperature in argon, stirred this mixture 24 hours, with 981mg (10mmol) ethyl propiolate and 7.5mL (7.5mmol) 1.0M ethylaluminum dichloride solution-treated and the restir 18 hours in hexane.The gained orange-red solution is added in batches in the 50% brinish mixture of 200mL ethyl acetate and 100mL, and fizz go down after, collect organic facies, water extracts with 3 * 100mL ethyl acetate again.The organic extract that merges is with the 50% salt water washing of 2 * 100mL, drying (Na ₂SO ₄) and evaporation, obtaining 5.76g pale red jelly, it is gone up at 120g silica gel (40-65 μ m order, 3.5cm diameter post) through flash chromatography and carries out purification with the solution of 10% ethyl acetate in hexane as eluant, collects the 20-mL flow point.Flow point 21-32 merging and evaporation are obtained the 2.18g crude product.By HPLC (15-30 μ m order silica gel, 50cm * 50mm post, flow velocity 70mL/min) be further purified as eluant with the solution of 7.5% ethyl acetate in hexane, obtain 1.62g (32%) title compound, RT 25 minutes is faint yellow gluey thing: [α] ²⁵ _D+ 83.50 ° (EtOH, c=0.98); UV (MeOH) 284 (ε=28,173), 207 (ε=16,884) nm; IR (CHCl ₃) 1708,1651,1628cm ^-1 ¹H NMR (CDCl ₃) δ 0.006 (6H, s), 0.80,3H, s), 0.88 (9H, s), 1.16 (1H, t, J=7.6Hz), 1.28 (6H, overlapping t, J=7Hz), 1.67-1.78, (6H, m), 2.16 (1H, t, J=9Hz), 3.00, (1H, dd, J=6,16, Hz), 3.35 (1H, dd, J=16,4Hz), 4.02 (1H, s), 4.16 (4H, overlapping q, J=7Hz), 5.75 (1H, d, J=16Hz), 5.84 (1H, d, J=15Hz), 6.17 (1H, d, J=11Hz), 6.88 (1H, dt, J=16,6Hz), 7.50 (1H, dd, J=11,15, Hz); MS (EI) m/z 504 (M ⁺, 23).Analytical calculation value C ₂₉H ₄₈O ₅Si:C, 69.00; H, 9.58; Si, 5.56.Measured value: C, 68.94; H, 9.69; Si, 5.67.

[1R-(1 α, 3a β, 4 α, 7a α)]-5-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl] ethylazelaate

With 1.009g (the 2.0mmol) [1R-[1 α (2E that stirs, 4E, 7E), 3a β, 4 α, 7a α]]-5-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl]-2,4, the hydrogenation on the 10% palladium/carbon at 200mg under room temperature and the atmospheric pressure of the 7-solution of three enedioic acid diethylesters in the ninth of the ten Heavenly Stems in the 50mL ethyl acetate stops (2.5 hours absorbed 140mL hydrogen) until absorption of hydrogen.This mixture filters through diatomite layer, washs with 4 * 50mL ethyl acetate, and filtrate and the cleaning mixture evaporation that merges obtained the colourless grease of 1.07g.It is gone up at 60g silica gel (40-65 μ m order, 3.5cm diameter post) through flash chromatography and carries out purification with the solution of 12% ethyl acetate in hexane as eluant, collects the 20-mL flow point.Flow point 7-12 is merged and evaporation, obtain 964mg (94%) title compound, be colorless oil: [α] ²⁵ _D+ 32.1 ° of (CHCl ₃, c=1.04); IR (CHCl ₃) 1726cm ^-1 ¹HNMR (CDCl ₃) δ 0.00 (3H, s), 0.01 (3H, s), 0.87 (9H, s), 0.88 (3H, s), 1.27 (6H, t, J=7Hz), 1.28-1.90 (21H, m), 2.25 (4H, br t), 3.98 (1H, s), 4.11 (4H, q, J=7Hz); MS (FAB) m/z 511 (M ⁺+ 1,100).Analytical calculation value C ₂₉H ₅₄O ₅Si:C, 68.11; H, 10.66; Si, 5.50.Measured value: C, 68.21; H, 10.85; Si, 5.43.

[1R-(1 α, 3a β, 4 α, 7a α)]-6-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl]-2,10-dimethyl-2,10-hendecane glycol

[1R-(1 α to the 868mg that stirred (1.7mmol), 3a β, 4 α, 7a α)]-and 5-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl] ethylazelaate dropwise adds the diethyl ether solution of the 3.0M methyl-magnesium-bromide of refrigerative (ice bath) 5.0mL (15mmol) in the solution of the anhydrous THF of 12mL.At room temperature stir this mixture 45 minutes, and be cooled to 5 ℃, and by dropwise adding the saturated NH of 3.0mL ₄Cl solution comes the quencher reaction.When fizz disappear after, add 15mL ethyl acetate and the saturated NH of 15mL ₄Cl solution continues to stir 20 minutes, pours this mixture into 100mL ethyl acetate and the saturated NH of 50mL ₄Cl solution.Collect organic facies and with 3 * 60mL ethyl acetate aqueous phase extracted again.With the organic extract that the 50% salt water washing of 2 * 100mL merges, dry (Na ₂SO ₄), and evaporation obtains the colourless jelly of 814mg, its through flash chromatography at 100g silica gel (40-65 μ m order, 3.5cm diameter post) with the solution of 50% ethyl acetate in hexane as the eluant purification, collection 20-mL flow point.Flow point 19-20 is merged and evaporation, obtain 763mg (93%) title compound after the high vacuum dry (17 hours), be the colourless foam shape: [α] ²⁵ _D+ 35.8 ° (EtOH, c=1.02); IR (CHCl ₃) 3608cm ^-11H NMR (CDCl ₃) δ 0.00 (6H, s), 0.88 (9H, s), 0.90 (3H, s), 1.20 (12H, s), 1.23-1.90. (27H, m), 3.99 (1H, s); MS (EI) m/z 482 (3, M ⁺).Analytical calculation value C ₂₉H ₅₈O ₃Si:C, 72.14; H, 12.11; Si, 5.82.Measured value: C, 72.18; H, 11.99; Si, 5.69.

[1S-(1 α, 3a β, 4 α, 7a α)] octahydro-1-[5-hydroxyl-1-(4-hydroxy-4-methyl amyl group)-5-methyl hexyl]-7a-methyl-4H-indenes-4-alcohol

To [1R-(1 α that is contained in the 700mg (1.45mmol) in the Teflon bottle that stirred, 3a β, 4 α, 7a α)]-6-[4-[[(1, the 1-dimethyl ethyl) dimethylsilyl] the oxygen base] octahydro-7a-methyl isophthalic acid H-indenes-1-yl]-2,10-dimethyl-2,10-hendecane glycol is at 5mL THF and 15mL CH ₃Adding about 30% fluorine silicic acid aqueous solution of 3.0mL (according to A.S.Pilcher and P.DeShong, J.Org.Chem., 1993,58, the preparation of method described in 5130) in the solution of CN also at room temperature stirs this mixture 1.0 hours in argon.Silicate fluoride solution with four crowdes of 2.0-mL adds according to a hour interval then, and amounting to 11mL reagent and response time is 5 hours.Carefully pour this reactant mixture into 125mL ethyl acetate and the saturated KHCO of 75mL ₃In the mixture of aqueous solution.When fizz disappear after, collect organic facies and with 3 * 75mL ethyl acetate aqueous phase extracted again.With the 50% salt water washing organic extract of 125mL, dry (Na ₂SO ₄), and evaporation obtains the 534mg jelly, it is gone up with 70% ethyl acetate as the eluant purification at 70g silica gel (40-65 μ m order, 3.5cm diameter post) through flash chromatography, collection 20-mL flow point.Flow point 17-30 is merged, filter and evaporation, and residue was remained on fine vacuum following 4 hours, obtain 458mg (85%) title compound, be colourless foam: [α] ²⁵ _D+ 26.2 ° of (CHCl ₃, c=0.76); IR (CHCl ₃) 3608cm ^-1 ¹H NMR (CDCl ₃) δ 0.93 (3H, s), 1.21 (12H, s), 1.24-1.60 (24H, m), 1.79-1.95 (4H, m), 4.07 (1H, s); MS (FAB) m/z 369 (M ⁺+ H).

[1S-(1 α, 3a β, 7a α)] octahydro-1-[5-hydroxyl-1-(4-hydroxy-4-methyl amyl group)-5-methyl hexyl]-7a-methyl-4H-indenes-4-ketone

[1S-(1 α to the 400mg that stirred (1.08mmol), 3a β, 4 α, 7a α)] octahydro-1-[5-hydroxyl-1-(4-hydroxy-4-methyl amyl group)-5-methyl hexyl]-7a-methyl-4H-indenes-4-alcohol adds 1.30g (3.45mmol) pyridinium dichromate and at room temperature stirred this mixture 4.75 hours in the solution of 8.0mL dichloromethane.With 20mL Di Iso Propyl Ether dilution, restir 15 minutes also filters through diatomite layer.Wash this kieselguhr and filtrate and the cleaning mixture evaporation that merges obtained the 405mg pale yellow glue with 4 * 40mL Di Iso Propyl Ether, its through flash chromatography at 70g silica gel (40-65 μ m order, 3.5cm the diameter post) upward carry out purification as eluant, collect the 20-mL flow point with the solution of 75% ethyl acetate in hexane.Flow point 17-30 merging and evaporation are obtained colourless jelly, it was kept 4.5 hours under fine vacuum, obtain 372mg (94%) title compound, be colourless jelly: [α] ²⁵ _D0.45 ° (EtOH, c=0.92); IR (CHCl ₃) 3608,1706cm ^-1 ¹H NMR (CDCl ₃) δ 0.63 (3H, s), 1.22 (12H, s), 1.30-2.10 (22H, m), 2.20-2.28 (2H, m), 2.45 (1H, dd, J=7.6,11Hz); MS m/z 348 (M ⁺-18).

[1S-(1 α, 3a β, 7a α)] octahydro-7a-methyl isophthalic acid-[the 5-methyl isophthalic acid-[4-methyl-4-[(TMS) the oxygen base] amyl group]-the 5-[(TMS) the oxygen base] hexyl]-4H-indenes-4-ketone

[1S-(1 α to the 366.6mg that stirred (1.0mmol), 3a β, 7a α)] octahydro-1-[5-hydroxyl-1-(4-hydroxy-4-methyl amyl group)-5-methyl hexyl]-7a-methyl-4H-indenes-4-ketone adds 1.25mL (8.5mmol) in the solution of 10.0mL dichloromethane 1-(TMS) imidazo at room temperature stirs this mixture 4.25 hours in argon.With the dilution of 7.0mL water, restir 15 minutes, and pour in the 50% brinish mixture of 75mL ethyl acetate and 50mL.Collect organic facies and with 3 * 50mL ethyl acetate aqueous phase extracted again.With the organic extract that the 50% salt water washing of 3 * 75mL merges, dry (Na ₂SO ₄), and evaporation obtains water white oil, it is gone up at 65g silica gel (40-65 μ m order, 3.5cm diameter post) through flash chromatography and carries out purification with the solution of 20% ethyl acetate in hexane as eluant, collection 20-mL flow point.Flow point 5-7 is merged, be concentrated into about 5mL, 0.45 μ m filter (Millex-HV) filters and evaporation obtains water white oil, and it was kept 18 hours under fine vacuum, obtains 469mg (91%) title compound: [α] ²⁵ _D-3.21 ° of (CHCl ₃, c=0.87); IR (CHCl ₃); 1706cm ^-1 ¹HNMR (CDCl ₃) δ 0.01 (18H, s), 0.63 (3H, s), 1.20 (6H, s), 1.21 (6H, s), 1.26-1.49 (14H, m), 1.50-2.10 (8H, m), 2.21-2.31 (2H, m), 2.46 (1H, dd, J=12,11Hz); MS (EI) m/z 495 (M ⁺-15).Analytical calculation value C ₂₉H ₅₈O ₃Si ₂: C, 68.17; H, 11.44; Si, 10.99.Measured value: C, 68.19; H, 11.41; Si, 11.07.

(1 α, 3 β, 5Z, 7E)-and 21-(3-hydroxy-3-methyl butyl)-9,10-open loop gallbladder steroid-5,7,10, (19)-triolefin-1,3,25-triol

Reagent [3R-(3 α to refrigerative (78 ℃) 571mg (1.0mmol) that stirred, 5 β, Z)]-[3,5-two [[(1, the 1-dimethyl ethyl) dimethylsilyl] oxygen base] ring caproic subunit] ethyl] diphenyl phosphine oxide adds the solution of 1.6M n-BuLi in hexane of 0.65mL (1.04mmol) in the solution of the anhydrous THF of 6.0mL.Stirred the gained dark red solution 10 minutes at-78 ℃, [1R-(1 α with 204.4mg (0.40mmol), 3a β, 7a α)] oxygen base octahydro-7a-methyl isophthalic acid-[5-methyl isophthalic acid-[4-methyl-4-[(TMS) oxygen base] amyl group]-5-[(TMS)] hexyl]-solution of 4H-indenes-4-ketone in the anhydrous THF of 2.5mL handles, and stirred 3 hours at-78 ℃.This mixture is heated to room temperature, stirred 15 minutes and used the 1N Rochelle salt solution of 15mL and the KHCO of 1N ₃1: 1 mixture quencher of solution reaction.After 10 minutes, pour this mixture into the 1N Rochelle salt solution of 70mL ethyl acetate and 40mL and the KHCO of 1N ₃In 1: 1 the mixture of solution.Separate organic facies and with 3 * 70mL ethyl acetate aqueous phase extracted again.With the organic extract that the 10% salt water washing of 100mL merges, dry (Na ₂SO ₄), and evaporate to dryness obtains 760mg and do not have coloring agent, its through purified by flash chromatography at 60 gram silica gel (40-65 μ m orders; 3.5cm the diameter post) go up with the solution of 5% ethyl acetate in hexane collection 15mL flow point as eluant.Flow point 5-10 merged and evaporate to dryness obtains 304mg and do not have coloring agent.The latter is dissolved among the THF of 4.0mL, uses the THF solution-treated of the 1.0M tetra-n-butyl ammonium fluoride of 5.0mL, and this solution was at room temperature stirred 42 hours in argon.With the dilution of 15mL water, stirred 15 minutes, and pour in the 10% brinish mixture of 75mL ethyl acetate and 50mL.Separate organic facies and with 3 * 70mL ethyl acetate aqueous phase extracted again.With the organic extract that 5 * 100mL water washing merges, dry (Na ₂SO ₄) and evaporation obtain the 186mg semisolid, its through flash chromatography at 50g silica gel (40-65 μ m order; 3.5cm the diameter post) ethyl acetate solution of going up with the 7.5%2-propanol carries out purification as eluant, collects the 15-mL flow point.Flow point 11-29 is merged and evaporate to dryness.Residue is dissolved in the 20mL anhydrous formic acid methyl ester and this solution is filtered through 0.4 μ m filter.Evaporated filtrate obtains the 154mg title compound, is colorless solid: [α] ²⁵ _D+ 50.93 ° (MeOH, c=0.32); ¹H NMR (CDCl ₃) δ 0.54 (3H, s), 1.21 (12H, s), 1.2-2.0 (27H, m), 2.20 (2H, m) 2.48 (1H, d, J=12Hz), 2.25 (2H, m), 2.82 (1H, s), 4.06 (1H, br s), 4.10 (1H, br s), 5.85 (1H, d, J=12Hz), 6.30 (1H, d, J=12Hz); MS (FAB) m/z 490.4 (M ⁺, 30).

Embodiment 3

1,25-dihydroxy-20-(4-hydroxy-4-methyl-amyl group) cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-(5-methyl isophthalic acid-methylene-5-TMS oxygen base-hexyl)-octahydro-indenes

The 6-[(1R of 1.78g (4.510mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-methyl-heptan-pure and mild 15mL dichloromethane of 6-alkene-2-.1-(TMS) imidazoles that dropwise adds 1.98mL (13.53mmol).At room temperature stirred this mixture 2 hours.Add 15mL water and stirred this mixture 10 minutes.Dissolve the gained mixture by adding 100mL water.With 50mL dichloromethane extraction water layer three times.With the organic layer that the water washing of 30mL salt merges, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 2.037g (96%) product, are water white oil.

2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-methyl-4-TMS oxygen base-amyl group)-cyclopropane-carboxylic acid ethyl ester

(the 1R of 1.275g (2.731mmol) packs in a 100mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-Rh of 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-(5-methyl isophthalic acid-methylene-5-TMS oxygen base-hexyl)-octahydro-indenes, 25mg ₂(OAc) ₄With the 10mL dichloromethane.At room temperature dropwise add the solution of (5mL/ hour) 935mg (8.202mmol) ethyl diazoacetate in the 20mL dichloromethane.Stirred this mixture 30 minutes.With this reactant mixture vacuum concentration, and with remaining residue through chromatography at pillar (100cm ³) go up and use dichloromethane as mobile phase eluting purification, obtaining 1.236g (82%) product, it is a mixture of isomers.

2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-cyclopropane-carboxylic acid ethyl ester

The 2-[(1S of 1.236g (2.235mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-solution and the 4mL oxolane of 1M tetrabutylammonium in oxolane of 2-(4-methyl-4-TMS oxygen base-amyl group)-cyclopropane-carboxylic acid ethyl ester, 4mL.At room temperature stirred this reactant mixture 2 hours.Dissolve this mixture and use 50mL water by adding the 100mL ethyl acetate: saline (2: 1) and the extraction of 50mL saline five times, use Na ₂SO ₄Dry and evaporation obtains the 1.081g product, is water white oil (product is directly used in next reaction without purification).

5-{1-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-hydroxymethyl-cyclopropyl }-2-methyl-penta-2-alcohol

The 2-[(1S of thick (about 2.2mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-cyclopropane-carboxylic acid ethyl ester and 6mL oxolane.The tetrahydrofuran solution that dropwise adds the 1M lithium aluminium hydride reduction of 6mL also at room temperature stirred this reactant mixture 1.5 hours.Then this flask is placed ice bath and dropwise add 5mL water.By adding the 1M H of 50mL saturated ammonium chloride solution, 50mL water and 25mL ₂SO ₄Dissolve this mixture, use 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.Residue is at silica gel (350cm ³) go up and use hexane: ethyl acetate (2: 1,1: 1) eluting purification, obtain 876mg (90%) product, it is an isomer mixture.

2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-cyclopanecarboxaldehyde

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 575mg (2.667mmol) pyridinium chlorochromate, 650mg kieselguhr and 12mL dichloromethane.The 5-{1-[(1S that dropwise adds 562mg (1.128mmol), 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-hydroxymethyl-cyclopropyl }-the 2-methyl-solution of penta-2-alcohol in the 4mL dichloromethane, and at room temperature stirred this mixture 2 hours.With this reactant mixture through silica gel (50cm ³) post and kieselguhr (3cm) is with dichloromethane, dichloromethane: ethyl acetate (4: 1,3: 1) is filtered.The flow point merging and the evaporation that will comprise product obtain the 550mg product, are yellow oil (product is directly used in next reaction without purification).

3-[2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-cyclopropyl]-ethyl acrylate

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 15mL toluene and add the tetrahydrofuran solution of the 1M potassium tert-butoxide of 4.5mL.Dropwise add the solution of 1.005g (4.482mmol) phosphonoacetic acid triethyl in 0.5mL toluene at about 5 ℃.At room temperature stirred this mixture 1 hour.Then this mixture is cooled to-15 ℃ and add thick (about 1.281mmol) 2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-solution of cyclopanecarboxaldehyde in 4mL toluene, and-10 ℃ of continuation stirrings 4 hours.With this reactant mixture of 50mL saturated ammonium chloride solution quencher and with the dilution of 50mL ethyl acetate, with 50mL ethyl acetate extraction inorganic layer twice, with the water washing of 25mL salt, dry and evaporation.Residue is at silica gel (150cm ³) going up and use hexane: ethyl acetate (5: 1,3: 1) obtains 518mg (two step gross production rates are 80%) product as mobile phase eluting purification, and it is an isomer mixture.

5-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-9-hydroxyl-5,9-dimethyl-ethyl caprate

3-[2-[(1S with 550mg (1.085mmol), 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2-(4-hydroxy-4-methyl-amyl group)-cyclopropyl]-ethyl acrylate in 4mL ethanol at ambient temperature on the 10%Pd/C of 200mg and hydrogen-pressure under hydrogenation.This reaction is by TLC (hexane: ethyl acetate-3: 1) indicate.After-filtration removed catalyst and evaporating solvent in 16 hours.Residue is at silica gel (100cm ³) go up and use hexane: ethyl acetate (10: 1,8: 1,3: 1) as mobile phase eluting purification, obtain 549mg (99%) product, be water white oil (isomer mixture).

6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2,6,10-trimethyl-hendecane-2,10-glycol

The 5-[(1R of 1.099mg (2.151mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-9-hydroxyl-5,9-dimethyl-ethyl caprate and 15mL ether.This solution is cooled off and dropwise adds the diethyl ether solution of the 3.12M methyl-magnesium-bromide of 4.10mL (12.792mmol) in ice-water bath.At room temperature stirred this mixture after adding 3.5 hours and then in ice bath, cool off.Dropwise add the 10mL saturated ammonium chloride solution.Dissolve the gained precipitation by adding 50mL water.Water layer extracts three times with the 50mL ethyl acetate again.The ether layer Na that merges ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (200cm ³) go up and use hexane: ethyl acetate (3: 1,2: 1,1: 1) carry out purification as mobile phase.The mixture flow point is repeated this chromatography (200cm ³) obtain 1.017g (95%) product, be water white oil.

c＝0.36，CHCl ₃

¹H NMR(CDCl ₃)：3.98(1H，br s)，2.00-1.95(1H，m)，1.84-1.73(1H，m)，1.66-1.63(1H，m)，1.60-1.47(4H，m)，1.43-1.30(11H，m)，1.29-1.14(8H，m)，1.20(12H，s)，1.04(3H，s)，0.90(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹³C NMR(CDCl ₃)：71.07，71.05，69.67，57.05，53.05，45.03，44.98，43.82，41.63，39.87，39.37，39.31，34.44，29.45，29.39，29.36，29.33，25.89，23.09，22.87，21.99，18.47，18.11，17.97，17.86，16.78，-4.69，-5.04

MS HRES value of calculation: C ₃₀H ₆₀O ₃Si[M+Na] ⁺519.4204

Measured value: [M+Na] ⁺519.4203

6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-2,6,10-trimethyl-hendecane-2,10-glycol

The 6-[(1R of 884mg (1.779mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2,6,10-trimethyl-hendecane-2, the tetrahydrofuran solution of the 1M tetrabutylammonium of 10-two pure and mild 10mL.Stirred this reactant mixture 48 hours down at 70 ℃.(tetrahydrofuran solution that adds the 1M tetrabutylammonium of new a collection of 5mL after 24 hours).Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (175cm ³) going up and use hexane: ethyl acetate (2: 1,1: 1) obtains 590mg (87%) product as mobile phase eluting purification, is water white oil.

c＝0.35，CHCl ₃

¹H NMR(CDCl ₃)：4.07(1H，brs)，2.02(1H，br d，J＝12.6Hz)，1.84-1.76(2H，m)，1.64-1.16(24H，m)，1.21(12H，s)，1.06(3H，s)，0.91(3H，s)

(1R, 3aR, 4S, 7aR)-and 1-[5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1,5-dimethyl-hexyl]-7a-methyl-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1.745g (4.638mmol) pyridinium dichromate, 2.00g kieselguhr and 15mL dichloromethane.The 6-[(1R that dropwise adds 590mg (1.542mmol), 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-2,6,10-trimethyl-hendecane-2, the solution of 10-glycol in the 4mL dichloromethane, and at room temperature stirred this mixture 5 hours.With this reactant mixture through silica gel (50cm ³) and kieselguhr (3cm) post with dichloromethane, dichloromethane: ethyl acetate (2: 1,1: 1) is filtered as mobile phase.The flow point that will comprise product merges and evaporation, obtains the ketone of 577mg (98%).

(1R, 3aR, 4S, 7aR)-and 1-[1,5-dimethyl-1-(4-methyl-4-TMS oxygen base-amyl group)-5-TMS oxygen base-hexyl]-7a-methyl-octahydro-indenes-4-ketone

(the 1R of 577mg (1.516mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 1-[5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1,5-dimethyl-hexyl]-7a-methyl-octahydro-indenes-4-ketone and 10mL dichloromethane.1-(TMS) imidazoles that dropwise adds 1.80mL (12.269mmol).At room temperature stirred this mixture 2 hours 30 minutes.Dissolve the gained mixture by adding 100mL water.With 50mL ethyl acetate extraction water layer four times.With the organic layer that the water washing of 50mL salt merges, use Na ₂SO ₄Dry also evaporation.

Residue is at silica gel (50cm ³) going up and use hexane: ethyl acetate (10: 1) obtains 739mg (93%) product as mobile phase eluting purification, is water white oil.

¹H NMR(CDCl ₃)：2.42(1H，dd，J＝9.9，7.3Hz)，2.30-2.13(3H，m)，2.04-1.50(9H，m)，1.42-1.14(11H，m)，1.21(6H，s)，1.20(6H，s)，0.90(3H，s)，0.73(3H，s)，0.11(9H，s)，0.10(9H，s)

1,25-dihydroxy-20-(4-hydroxy-4-methyl-amyl group) cholecalciferol

(the 1S of 700mg (1.201mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 5mL oxolane.This reactant mixture is cooled to-70 ℃, dropwise adds the 1.6M n-BuLi of 0.75mL (1.200mmol).Stirred the gained dark red solution 25 minutes down at-78 ℃, (the 1R that dropwise adds 300mg (0.571mmol), 3aR, 4S, 7aR)-and 1-[1,5-dimethyl-1-(4-methyl-4-TMS oxygen base-amyl group)-5-TMS oxygen base-hexyl]-the 7a-methyl-octahydro-indenes-solution of 4-ketone in the 1mL oxolane.Stirred this reactant mixture 5 hours, and removed cooling bath then and also this mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section four times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (20: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 430mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 5mL.At room temperature stirred this reactant mixture 24 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil.Should oil crystallization in methyl acetate, obtain 183mg (62%) product.

c＝0.40，EtOH

UVλmax(EtOH)：213nm(ε14606)，264nm(ε17481)

¹H NMR(CDCl ₃)：6.18(1H，d，J＝11.1Hz)，5.97(1H，d，J＝11.3Hz)，5.23(1H，d，J＝1.3Hz)，4.86(1H，d，J＝4.7Hz)，4.75(1H，d，J＝1.7Hz)，4.54(1H，d，J＝3.8Hz)，4.20-4.16(1H，m)，4.05(1H，s)，4.04(1H，s)，4.01-3.96(1H，m)，2.77(1H，br d，J＝11.7Hz)，2.35(1H，br d，J＝11.5Hz)，2.17(1H，dd，J＝13.5，5.2Hz)，2.01-1.94(2H，m)，1.83-1.78(1H，m)，1.68-1.52(6H，m)，1.48-1.05(16H，m)，1.06(12H，s)，0.86(3H，s)，0.60(3H，s)

¹³C NMR(CDCl ₃)：149.41，139.87，135.74，122.37，117.81，109.72，68.72，68.69，68.34，65.07，56.64，56.05，46.17，44.85，44.79，43.11，40.53，40.12，39.56，38.89，29.48，29.45，29.18，28.34，23.15，22.98，21.89，21.59，18.07，17.56，14.70

MS HRES value of calculation: C ₃₃H ₅₆O ₄[M+Na] ⁺539.4071

Measured value: [M+Na] ⁺539.4066

Embodiment 4

1,25-dihydroxy-20-(4-hydroxy-4-methyl-amyl group)-19-falls-cholecalciferol synthetic

1,25-dihydroxy-20-(4-hydroxy-4-methyl-amyl group)-19-falls-cholecalciferol

(the 1R of 1.023g (1.792mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 5mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi BuLi that also dropwise add 1.12mL (1.792mmol).Stirred the gained dark red solution 25 minutes at-78 ℃, (the 1R that adds 350mg (0.667mmol), 3aR, 4S, 7aR)-and 1-[1,5-dimethyl-1-(4-methyl-4-TMS oxygen base-amyl group)-5-TMS oxygen base-hexyl]-the 7a-methyl-octahydro-indenes-solution of 4-ketone in the 1mL oxolane.Stirred this reactant mixture 5 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.This mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section four times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (30: 1 and 10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 500mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 6mL.At room temperature stirred this reactant mixture 20 hours.The 1M tetrabutylammonium that adds new a collection of 3mL in oxolane solution and stirred this mixture 22 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and carry out purification as mobile phase with ethyl acetate.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (2 times) obtain 285mg (85%) product, be white solid.

c＝0.38，CHCl ₃

UVλmax(EtOH)：243nm(ε33019)，251nm(ε38843)，261nm(ε26515)

¹H NMR(CDCl ₃)：6.29(1H，d，J＝11.1Hz)，5.83(1H，d，J＝11.1Hz)，4.12-4.09(1H，m)，4.06-4.00(1H，m)，2.80-2.71(2H，m)，2.47(1H，dd，J＝13.3，3.1Hz)，2.23-2.17(2H，m)，2.05-1.91(3H，m)，1.78(1H，ddd，J＝13.1，8.3，3.1Hz)，1.67-1.16(24H，m)，1.21(12H，s)，0.89(3H，s)，0.63(3H，s)

¹³C NMR(CDCl ₃)：142.76，131.16，123.67，115.63，71.04，67.38，67.15，57.18，56.69，46.73，44.97，44.92，44.66，42.20，41.15，39.70，39.54，39.37，37.22，29.44，29.39，29.36，28.90，23.48，23.14，22.41，21.97，18.44，17.95，15.12

MS HRES value of calculation: C ₃₂H ₅₆O ₄[M+Na] ⁺527.4071

Measured value: [M+Na] ⁺527.4073

Embodiment 5

Synthesizing of 1 α-fluoro-25-hydroxyl-20-(4-hydroxy-4-methyl-amyl group)-cholecalciferol

1 α-fluoro-25-hydroxyl-20-(4-hydroxy-4-methyl-amyl group)-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 680mg (1.445mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 5mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.9mL (1.44mmol).Stirred the gained dark red solution 25 minutes at-78 ℃, (the 1R that dropwise adds 300mg (0.571mmol), 3aR, 4S, 7aR)-and 1-[1,5-dimethyl-1-(4-methyl-4-TMS oxygen base-amyl group)-5-TMS oxygen base-hexyl]-the 7a-methyl-octahydro-indenes-solution of 4-ketone in the 1mL oxolane.Stirred this reactant mixture 4 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.This mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (30: 1 and 10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 399mg), and its 1M tetrabutylammonium solution in oxolane with 5mL is handled.At room temperature stirred this reactant mixture 20 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (2: 1 and 3: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 243mg (82%) product, be the white foam shape.

c＝0.40，CHCl ₃

UVλmax(EtOH)：208nm(ε16024)，242nm(ε14965)，270nm(ε15024)

¹H NMR(CDCl ₃)：6.39(1H，d，J＝11.1Hz)，6.01(1H，d，J＝11.3Hz)，5.38(1H，s)，5.13(1H，ddd，J＝49.9，6.8，3.7Hz)，5.09(1H，s)，4.25-4.18(1H，m)，2.82-2.77(1H，m)，2.61(1H，dd，J＝13.3，3.7Hz)，2.30(1H，dd，J＝13.3，7.6Hz)，2.22-2.13(1H，m)，2.07-1.94(3H，m)，1.76-1.15(24H，m)，1.21(12H，s)，0.89(3H，s)，0.63(3H，s)

¹³C NMR(CDCl ₃)：143.30，143.06(d，J＝16.7Hz)，131.40，125.47，117.37，114.71(d，J＝9.9Hz)，91.53(d，J＝172.6Hz)，71.05，71.05，66.53，66.47，57.17，56.74，46.89，44.96，44.90，41.17，40.87，40.67，39.67，39.51，39.36，29.41，29.35，29.07，23.56，23.11，22.37，21.90，18.43，17.94，15.05

Embodiment 6

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls) cholecalciferol is synthetic

(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-1-[3-(tert-butyl group-dimethyl-silanyloxy base)-1-methylene-propyl group]-7a-methyl-octahydro-indenes

At one stirring rod is installed, has the 3-[(1R of 17.53g (51.77mmol) that pack in the 250mL round-bottomed flask of the Clarkson joint of rubber septum and nitrogen purging, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-the pure and mild 75mL dichloromethane of Ding-3-alkene-1-.Add 7.05g (103.54mmol) imidazo and add 9.36g (62.124mmol) tert-butyl group dimethylsilyl chloride subsequently.Stirred this mixture 2.5 hours.

Dilute this mixture and use 50mL dichloromethane extraction four times with 100mL water then.The organic layer Na that merges ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (400cm ³) going up with hexane, hexane: ethyl acetate (50: 1,25: 1) is as mobile phase eluting purification and collect about 40mL flow point, obtains 22.32g (95%) product, is water white oil.

¹H NMR(CDCl ₃)：4.87(1H，s)，4.80(1H，s)，4.02(1H，br s)，3.67(2H，t，J＝7.3Hz)，2.34-2.14(2H，m)，2.06-2.00(1H，m)，1.85-1.27(9H，m)，1.20-1.08(2H，m)，0.89(18H，s)，0.79(3H，s)，0.05(6H，s)，0.02(3H，s)，0.01(3H，s).

2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-the cyclopropane-carboxylic acid ethyl ester

(the 1R of 10.00g (22.08mmol) packs in a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-1-[3-(tert-butyl group-dimethyl-silanyloxy base)-1-methylene-propyl group]-Rh of 7a-methyl-octahydro-indenes, 200mg ₂(OAc) ₄With the 40mL dichloromethane.At room temperature dropwise add the solution (12mL/ hour) of 5.304g (46.486mmol) ethyl diazoacetate in the 30mL dichloromethane.With this reactant mixture concentrating under reduced pressure and with remaining residue at pillar (200cm ³) going up and use hexane: ethyl acetate (1: 1) is filtered as mobile phase.Evaporating solvent and with the oily residue through chromatography at pillar (250cm ³) going up and use hexane: ethyl acetate (25: 1,10: 1 and 5: 1) obtains 8.44g (71%) product as mobile phase eluting purification, is isomer mixture.

2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-methanol

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl of 4.140g (7.682mmol)]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropane-carboxylic acid ethyl ester and 20mL dichloromethane.This reactant mixture is cooled to-70 ℃ and dropwise added the toluene solution of the 1.5M DIBAL-H of 10.0mL (15.0mmol) in 45 minutes.Stir this reactant 1 hour at-70 ℃, dropwise add the 5mL saturated ammonium chloride solution then.

Dissolve this mixture by the 1N HCl that adds 100mL water and 50mL, use 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (200cm ³) going up and use hexane: ethyl acetate (10: 1,3: 1) is as mobile phase eluting purification.To comprise the flow point merging of product and the product (isomer mixture) that evaporation obtains 3.610g (94%), be water white oil.

2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopanecarboxaldehyde

In a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium chlorochromate, 7.00g kieselguhr and the 100mL dichloromethane of 6.074g (28.178mmol).Dropwise add 6.970g (14.027mmol) 2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-solution of methanol in the 10mL dichloromethane, and at room temperature stirred this mixture 1 hour.With this reactant mixture at silica gel (200cm ³) and kieselguhr (2cm) post on filter as mobile phase with dichloromethane.The flow point merging and the evaporation that will comprise product obtain grease (about 5.71g).Product is directly used in next reaction without purification.

3-{2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-ethyl acrylate

In a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 80mL toluene and add the solution of 1M potassium tert-butoxide in oxolane of 35.0mL (35.0mmol).Under about 5 ℃, dropwise add the solution of 7.850g (35.015mmol) phosphonoacetic acid triethyl in 5mL toluene.At room temperature stirred this mixture 1 hour.Then this mixture is cooled to-15 ℃ of 2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyls that also add thick (about 11.54mmol)]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-solution of cyclopanecarboxaldehyde in 5mL toluene, and-10 ℃ of continuation stirrings 3 hours.With this reactant mixture of 10mL saturated ammonium chloride solution quencher, with 100mL saturated ammonium chloride solution dilution and with 50mL toluene, use the 50mL ethyl acetate extraction four times subsequently.With 50mL salt water washing organic layer, dry and evaporation.Residue is at silica gel (200cm ³) going up and use hexane: ethyl acetate (20: 1) obtains 5.750g (88%) product (isomer mixture) as mobile phase eluting purification.

7-(tert-butyl group-dimethyl-silanyloxy base)-5-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-5-methyl-cognac oil

At room temperature with 3-{2-[2-(tert-butyl group-dimethyl-silanyloxy base)-ethyl of 5.750g (10.177mmol)]-2-[(1S, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-ethyl acrylate carrying out hydrogenation under hydrogen-pressure on the 10%Pd/C of 1.60g in 40mL ethanol.This reaction is indicated (hexane: ethyl acetate-50: 1) by thin layer chromatography.After-filtration removed catalyst and evaporating solvent in 18 hours.Residue is at silica gel (300cm ³) go up and use hexane: ethyl acetate (100: 1,50: 1,20: 1) as mobile phase eluting purification, obtain the product (isomer mixture) of 5.150g (89%).

8-(tert-butyl group-dimethyl-silanyloxy base)-6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2,6-dimethyl-octane-2-alcohol

At one stirring rod is installed, has 7-(tert-butyl group-dimethyl-silanyloxy base)-5-[(1R of 5.110g (8.980mmol) that pack in the 250mL round-bottomed flask of Clarkson joint of rubber septum, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-5-methyl-cognac oil and 80mL ether.In ice-water bath, cool off this solution, dropwise add the solution of 3.12M methyl-magnesium-bromide in ether of 17.4mL (54.3mmol).At room temperature stirred this mixture after adding 2.5 hours, cooling once more in ice bath then.Dropwise add the 10mL saturated ammonium chloride solution.Dissolve the gained precipitation by adding the 50mL saturated ammonium chloride solution.With 100mL ethyl acetate extraction water layer three times.With the organic layer drying (Na that merges ₂SO ₄) and evaporation.This product need not be further purified and be directly used in next reaction.

3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-3,7-dimethyl-octane-1,7-glycol

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 8-(tert-butyl group-dimethyl-silanyloxy base)-6-[4-(tert-butyl group-dimethyl-silanyloxy the base)-7a-methyl-octahydro-indenes-1-yl of thick (about 8.98mmol)]-2, the solution of 1M tetrabutylammonium in oxolane of 6-dimethyl-octane-2-alcohol, 10mL oxolane and 15.0mL (15.0mmol).At room temperature stirred this reactant mixture 2.5 hours.Dissolve this mixture by adding the 150mL ethyl acetate, and use 50mL water: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.This oily residue is at pillar (400cm ³) going up and to use hexane: ethyl acetate (1: 1) is as mobile phase chromatogram purification four times, obtain: one: 1.456g (low polar isomer), two: 0.852g (isomer mixture), three: 1.132g (strong polar isomer), all product 3.440g (two step gross production rates are 88%).

Low polar isomer: (3S)-3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-3,7-dimethyl-octane-1,7-glycol

c＝0.44，CHCl ₃

¹H NMR(CDCl ₃)：3.90(1H，br s)，3.67(2H，br t，J＝8.1Hz)，2.06-1.99(1H，m)，1.87-1.50(4H，m)，1.73(2H，t，J＝7.9Hz)，1.40-1.06(14H，m)，1.22(6H，s)，1.06(3H，s)，0.95(3H，s)，1.95-0.82(1H，m)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹³C NMR(CDCl ₃)：71.03，69.58，59.79，57.32，52.99，44.78，43.81，41.64，41.58，40.26，38.68，34.37，29.48，29.36，25.86，23.49，22.78，21.72，18.18，18.09，17.78，16.78，-4.70，-5.07

MS HRES value of calculation: C ₂₆H ₅₂O ₃Si [M+Na] ⁺463.3578

Measured value: [M+Na] ⁺463.3580

Strong polar isomer: (3R)-3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-3,7-dimethyl-octane-1,7-glycol

c＝0.44，CHCl ₃

¹H NMR(CDCl ₃)：3.99-3.97(1H，m)，3.65-3.61(2H，m)，1.97(1H，br d，J＝12.3Hz)，1.84-1.72(1H，m)，1.66-1.50(6H，m)，1.45-1.15(14H，m)，1.21(6H，s)，1.05(3H，s)，0.95(3H，s)，0.87(9H，s)，-0.01(3H，s)，-0.02(3H，s)

¹³C NMR(CDCl ₃)：71.05，69.57，59.47，57.46，53.02，44.87，43.90，41.83，41.61，39.99，38.93，34.37，29.43，29.42，25.87，23.42，22.84，22.12，18.57，18.09，17.81，16.79，-4.69，-5.06

MS HRES value of calculation: C ₂₆H ₅₂O ₃Si [M+Na] ⁺463.3578

Measured value: [M+Na] ⁺463.3575

(3S)-and 3-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-7-hydroxyl-3,7-dimethyl-octanal

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1.572g (7.292mmol) pyridinium chlorochromate, 1.60g kieselguhr and 25mL dichloromethane.(the 3S)-3-[(1R that dropwise adds 1.607g (3.646mmol), 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-3,7-dimethyl-octane-1, the solution of 7-glycol in the 6mL dichloromethane also at room temperature stirred this mixture 1 hour 45 minutes, added 300mg (1.392mmol) pyridinium chlorochromate of another batch then.This reactant of restir 1 hour 15 minutes.With this reactant mixture at silica gel (50cm ³) and kieselguhr (1cm) post on dichloromethane, dichloromethane: ethyl acetate (4: 1) is filtered.The flow point merging and the evaporation that will comprise product obtain the 1.58g product, are yellow oil.This product need not be further purified and be directly used in next step.

(6S)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2,6-dimethyl-ninth of the ten Heavenly Stems-8-alkynes-2-alcohol

(3S)-3-[(1R of 1.58g (3.601mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-7-hydroxyl-3,7-dimethyl-octanal and 30mL methanol.1-diazo-2-oxo-the propyl group that adds 1.416g (7.37mmol))-solution of phosphonic acids dimethyl esters in 3mL methanol, and the gained mixture cooled off in ice bath.Add 1.416g (10.245mmol) potassium carbonate and also this reactant mixture was stirred in ice bath 30 minutes, at room temperature stirred then 3 hours.Add 100mL water and use this mixture of 80mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (250cm ³) going up and use hexane: ethyl acetate (7: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 1.310g (two step gross production rates are 83%) product, are water white oil.

c＝0.61，CHCl ₃

¹H NMR(CDCl ₃)：3.98(1H，br s)，2.28(2H，d，J＝2.1Hz)，1.95-1.91(2H，m)，1.78(1H，dt，J＝13.4，3.8Hz)，1.68-1.62(1H，m)，1.58-1.48(6H，m)，1.44-1.17(15H，m)，1.22(6H，s)，1.04(3H，s)，1.00(3H，s)，0.93-0.83(1H，m)，0.88(9H，s)，-0.00(3H，s)，-0.01(3H，s)

¹³C NMR(CDCl ₃)：83.09，71.03，69.84，69.64，56.68，52.95，44.80，43.71，41.31，40.21，39.28，34.33，29.44，29.29，28.80，25.85，22.74，22.69，22.18，18.14，18.05，17.73，16.68，-4.77，-5.13

MS HRES value of calculation: C ₂₇H ₅₀O ₂Si [M+Na] ⁺457.3472

Measured value: [M+Na] ⁺457.3473

(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-1-[(1S)-1,5-dimethyl-1-Propargyl-5-TMS oxygen base-hexyl]-7a-methyl-octahydro-indenes

(6S)-6-[(1R of 1.300g (2.990mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2, the 6-dimethyl-ninth of the ten Heavenly Stems-pure and mild 25mL dichloromethane of 8-alkynes-2-.1-(TMS) imidazoles that dropwise adds 2.00mL (13.63mmol).At room temperature stirred this mixture 1 hour.

Add 100mL water and use this mixture of 80mL hexane extraction three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate (25: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 1.409g (93%) product, are water white oil.

¹H NMR(CDCl ₃)：3.98(1H，br s)，2.27(2H，d，J＝2.9Hz)，1.97-1.91(2H，m)，1.82-1.75(1H，m)，1.69-1.62(1H，m)，1.59-1.50(2H，m)，1.42-1.20(12H，m)，1.20(6H，s)，1.05(3H，s)，1.00(3H，s)，0.93-0.85(1H，m)，0.88(9H，s)，0.10(9H，s)，0.00(3H，s)，-0.01(3H，s)

(6S)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three fluoro-6,10-dimethyl-2-Trifluoromethyl-1 0-TMS oxygen base-11-3-alkynes-2-alcohol

Stirring rod is being installed, is having (the 1R of 1.390g (2.742mmol) that pack in the 50mL two neck round-bottomed flasks of the Clarkson joint of rubber septum and funnel (band cooling bath), 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-1-[(1S)-1,5-dimethyl-1-Propargyl-5-TMS oxygen base-hexyl]-7a-methyl-octahydro-indenes and 30mL oxolane.Funnel is linked to each other with the container that Hexafluoro acetone is housed and cool off (acetone, dry ice).This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 5.00mL (8.00mmol).Add Hexafluoro acetone (valve open of container three times) after 30 minutes.Stir this reactant at-70 ℃ and added the 5.0mL saturated ammonium chloride solution in 2 hours then.Dissolve this mixture and use 80mL ethyl acetate extraction three times by adding the 100mL saturated ammonium chloride solution, use Na ₂SO ₄Dry also evaporation.With twice of oily residue chromatographic isolation to remove a large amount of polymer compounds.First pillar (100cm ³) use hexane: ethyl acetate (10: 1) is as mobile phase.Second pillar (100cm ³) use hexane: ethyl acetate (25: 1,15: 1) is as mobile phase.The flow point merging and the evaporation that will comprise product obtain the 1.959g water white oil.Product need not be further purified and be directly used in next step.

(6S)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2,10-glycol

(the 6S)-6-[(1R of thick (about 2.74mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three fluoro-6, the solution of 1M tetrabutylammonium in oxolane of 10-dimethyl-2-Trifluoromethyl-1 0-TMS oxygen base-pure and mild 12.0mL of 11-3-alkynes-2-(12.0mmol), and at 70 ℃ of these reactants of stirring.The solution of 1M tetrabutylammonium in oxolane that adds new a collection of 5.0mL after 18 hours.This reactant mixture of 70 ℃ of restir 80 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (200cm ³) going up and use hexane: ethyl acetate (3: 1,2: 1) is as mobile phase eluting purification.The flow point that will comprise product merges and evaporation.Residue crystallization in hexane-ethyl acetate is obtained 917mg (two step gross production rates are 69%) product, be white crystals.

m.p.146-147℃

c＝0.43，CHCl ₃

¹H NMR(CDCl ₃)：4.08(1H，br s)，2.45(1H，AB，J＝17Hz)，2.36(1H，AB，J＝17Hz)，1.98-1.92(1H，m)，1.85-1.74(2H，m)，1.67-1.18(18H，m)，1.25(6H，s)，1.07(3H，s)，1.02(3H，s)

MS HRES value of calculation: C ₂₄H ₃₆F ₆O ₃[M+Na] ⁺509.2461

Measured value: [M+Na] ⁺509.2459

(1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-own-3-alkynyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into (6S)-1 of 300mg (0.617mmol), 1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2,10-two pure and mild 10mL dichloromethane.Add 696mg (1.851mmol) pyridinium dichromate and 710mg kieselguhr and at room temperature stirred this mixture 3 hours.With this reactant mixture at silica gel (50cm ³) and kieselguhr (2cm) post on use dichloromethane: ethyl acetate (4: 1) is filtered as mobile phase.The flow point merging and the evaporation that will comprise product obtain yellow oil.This product need not be further purified and be directly used in next step.

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls) cholecalciferol

(the 1S of 1.798g (3.084mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 12mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 1.9mL (3.04mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds thick (about 0.617mmol), 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours, and removed cooling bath then and in this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up and use hexane: ethyl acetate (5: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (293mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 5mL.At room temperature stirred this reactant mixture 40 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain 190mg (three step gross production rates are 50%) product, be the white foam shape.

c＝0.35，CHCl ₃

UV λmax(EtOH)：205.50nm(ε16586)，266.00nm(ε14319)

¹H NMR(CDCl ₃)：6.36(1H，d，J＝11.3Hz)，6.23(1H，br s)，6.00(1H，d，J＝11.1Hz)，5.32(1H，s)，4.98(1H，s)，4.43(1H，dd，J＝7.7，4.3Hz)，4.25-4.20(1H，m)，2.82-2.79(1H，m)，2.59(1H，dd，J＝13.1，3.1Hz)，2.44(1H，AB，J＝17.2Hz)，2.37(1H，AB，J＝17.2Hz)，2.30(1H，dd，J＝13.2，6.2Hz，)，2.06-1.87(4H，m)，1.72-1.36(11H，m)，1.26-1.21(1H，m)，1.24(6H，s)，0.99(3H，s)，0.64(3H，s)

¹³C NMR(CDCl ₃)：147.48，142.29，133.16，124.72，121.32(q，J＝287.1Hz)，117.59，11.68，90.08，72.62，71.39，70.73，66.89，57.28，56.52，46.65，45.18，43.20，42.81，41.04，40.89，40.03，29.79，29.35，28.95，23.45，22.86，22.60，21.84，17.77，14.93

MS HRES value of calculation: C ₃₃H ₄₆F ₆O ₄[M+Na] ⁺643.3192

Measured value: [M+Na] ⁺643.3192

Embodiment 7

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-19-falls-cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-alkynyl]-octahydro-indenes-4-ketone

(the 1R of 585mg (1.207mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone and 10mL dichloromethane.1-(TMS) imidazoles that dropwise adds 1.5mL (10.2mmol).At room temperature stirred this mixture 3 hours.Add the 150mL ethyl acetate and use this mixture of 50mL water washing three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 660mg (87%) product, are water white oil.

¹H NMR(CDCl ₃)：2.44-2.39(3H，m)，2.32-2.16(2H，m)，2.10-1.99(2H，m)，1.95-1.84(2H，m)，1.77-1.56(4H，m)，1.38-1.19(7H，m)，1.20(6H，s)，1.03(3H，s)，0.74(3H，s)，0.28(9H，s)，0.10(9H，s)

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-19-falls-cholecalciferol

618mg (1 packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; (1R 083mmol); 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi BuLi that also dropwise add 0.67mL (1.07mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that adds 335mg (0.532mmol), 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours, and then dry ice was removed from cooling bath and in 1 hour, this solution is heated to-40 ℃.In this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section four times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 440mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 29 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (2 times) obtain 308mg (95%) product, be the white foam shape.

c＝0.42，EtOH

UVλmax(EtOH)：243nm(ε29530)，252nm(ε33645)，261nm(ε23156)

¹H NMR(CDCl ₃)：6.28(1H，d，J＝11.3Hz)，5.83(1H，d，J＝11.1Hz)，4.12-4.09(1H，m)，4.05-4.01(1H，m)，2.80-2.72(2H，m)，2.46(1H，dd，J＝13.4，3.0Hz)，2.42(1H，AB，J＝16.8Hz)，2.36(1H，AB，J＝16.8Hz)，2.22-2.16(2H，m)，2.04-1.86(6H，m)，1.80-1.38(17H，m)，1.23(6H，s)，0.99(3H，s)，0.63(3H，s)

¹³C NMR(CDCl ₃)：142.13，131.41，123.55，121.36(q，J＝286.9Hz，115.88，72.40，71.40，67.40，67.15，27.19，56.47，46.50，44.44，43.40，41.94，40.91，40.83，39.97，37.09，29.65，29.29，29.26，28.79，23.35，22.79，22.60，21.81，17.79，15.00

MS HRES value of calculation: C ₃₂H ₄₆F ₆O ₄[M+Na] ⁺631.3192

Measured value: [M+Na] ⁺631.3191

Embodiment 8

(20S)-1 α-fluoro-25-hydroxyl-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol synthetic

(20S)-1 α-fluoro-25-hydroxyl-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 495mg (1.052mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.65mL (1.04mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that dropwise adds 300mg (0.477mmol), 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.This mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 429mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 18 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (1: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product is dissolved in methyl acetate and evaporates the product that (2 times) obtain 274mg (92%), be the white foam shape.

c＝0.50，EtOH

UVλmax(EtOH)：212nm(ε34256)，243nm(ε15866)，271nm(ε16512)

¹H NMR(CDCl ₃)：6.38(1H，d，J＝11.3Hz)，6.01(1H，d，J＝11.3Hz)，5.38(1H，s)，5.13(1H，ddd，J＝49.9，6.6，3.6Hz)，5.09(1H，s)，4.23-4.19(1H，m)，2.80(1H，dd，J＝12.0，3.5Hz)，2.61(1H，dd，J＝13.3，3.7Hz)，2.43(1H，AB，J＝16.9Hz)，2.36(1H，AB，J＝16.9Hz)，2.30(1H，dd，J＝13.4，7.9Hz)，2.24-2.15(1H，m)，2.04-1.92(3H，m)，1.73-1.35(17H，m)，1.26-1.21(1H，m)，1.24(6H，s)，0.99(3H，s)，0.64(3H，s)

¹³C NMR(CDCl ₃)：142.97(d，J＝16.8Hz)，142.69，131.68(d，J＝2.2Hz)，125.37，121.34(q，J＝286.9Hz)，117.63，114.99(d，J＝10.0Hz)，91.61(d，J＝172.4Hz)，90.07，72.62，71.38，66.56(d，J＝6.0Hz)，57.26，56.53，46.68，44.91，43.31，40.97，40.89，40.68(d，J＝20.6Hz)，40.01，29.67，29.28，28.98，23.43，22.81，22.60，21.78，17.79，14.96

MS HRES value of calculation: C ₃₃H ₄₅F ₇O ₃[M+Na] ⁺645.3149

Measured value: [M+Na] ⁺645.3148

Embodiment 9

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-(2Z)-thiazolinyls) cholecalciferol is synthetic

(3Z, 6S)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-glycol

In a 25mL round-bottomed flask, pack into (6S)-1,1 of 250mg (0.514mmol), 1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2, the 5%Pd/CaCO of 10-glycol, 70mg ₃, 6.0mL hexane, 2.4mL ethyl acetate and the solution (with 3.1mL ethanol and 168 μ l quinoline preparation) of 0.23mL quinoline in ethanol.This reaction substrate is carried out hydrogenation at ambient temperature in hydrogen-pressure.This reaction is indicated (hexane: ethyl acetate 2: 1) by thin layer chromatography.After-filtration removed catalyst and evaporating solvent in 7 hours.Residue is at silica gel (125cm ³) going up and use hexane: ethyl acetate (2: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 243mg (97%) product, are water white oil.

¹H NMR(CDCl ₃)：6.14-6.05(1H，m)，5.49(1H，d，J＝12.5Hz)，4.08(1H，br s)，2.83(1H，dd，J＝15.9，9.7Hz)，2.48-2.38(1H，m)，1.85-1.75(2H，m)，1.65-1.20(17H，m)，1.22(3H，s)，1.20(3H，s)，1.08(3H，s)，1.03-0.96(1H，m)，1.00(3H，s)

¹³C NMR(CDCl ₃)：140.22，117.44，71.79，69.66，56.74，52.58，44.11，43.45，41.19，40.24，39.64，36.88，33.44，30.09，28.88，22.55，22.21，21.70，17.63，17.58，16.54

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 3Z of 290mg (0.594mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 6S)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-two pure and mild 10mL dichloromethane.Add 700mg (1.861mmol) pyridinium dichromate and 750mg kieselguhr and at room temperature stirred this mixture 3 hours.With this reactant mixture at silica gel (75cm ³) and kieselguhr (2cm) post on use dichloromethane: ethyl acetate (4: 1) is filtered as mobile phase.The flow point merging and the evaporation that will comprise product obtain yellow oil.This product need not be further purified and be directly used in next step.

(20S)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-(2Z)-thiazolinyls) cholecalciferol

(the 1S of 1.800g (3.088mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 10.0mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 1.9mL (3.04mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 278mg (0.571mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours (last 0.5 hour under-20 ℃), remove cooling bath then, this mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up and use hexane: ethyl acetate (4: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (309mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 5mL.At room temperature stirred this reactant mixture 22 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain 192mg (two step gross production rates are 54%) product, be the white foam shape.

UVλmax(EtOH)：204.08nm(ε27522)，266.03nm(ε20144)

¹H NMR(CDCl ₃)：6.37(1H，d，J＝11.1Hz)，6.10(1H，ddd，J＝12.5，9.0，6.0Hz)，6.00(1H，d，J＝11.3Hz)，5.47(1H，d，J＝12.2Hz)，5.32(1H，s)，5.07(1H，br，s)，4.99(1H，s)，4.43(1H，dd，J＝7.8，4.2Hz)，4.25-4.20(1H，m)，2.85-2.79(2H，m)，2.59(1H，dd，J＝13.4，3.0Hz)，2.46(1H，dd，J＝16.4，4.9Hz)，2.31(1H，dd，J＝13.4，6.4Hz)，2.04-1.97(3H，m)，1.90(1H，ddd，J＝12.0，8.2，3.2Hz)，1.76-1.20(17H，m)，1.21(3H，s)，1.20(3H，s)，1.06-1.00(1H，m)，0,96(3H，s)，0.64(3H，s)

¹³C NMR(CDCl ₃)：147.51，142.74，140.17，132.92，124.88，122.95(q，J＝286.9Hz)，122.80(q，J＝285.5Hz)，117.52，117.39，111.65，71.94，70.73，66.88，56.86，56.65，46.79，45.20，43.95，42.83，41.06，40.09，39.75，37.22，30.35，29.05，28.82，23.58，22.50，22.19，21.93，17.53，15.04

MS HRES value of calculation: C ₃₃H ₄₈F ₆O ₄[M+Na] ⁺645.3349

Measured value: [M+Na] ⁺645.3350

Embodiment 10

(20S)-1,25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 1R of 590mg (1.213mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone and 15mL dichloromethane.1-(TMS) imidazoles that dropwise adds 1.4mL (9.5mmol).At room temperature stirred this mixture 4 hours.Add the 150mL ethyl acetate and use this mixture of 50mL water washing three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 726mg (95%) product, are water white oil.

¹H NMR(CDCl ₃)：6.07-5.99(1H，m)，5.41(1H，d，J＝11.4Hz)，2.52(2H，dd，J＝6.2，2.6Hz)，2.44-2.38(1H，m)，2.31-1.54(11H，m)，1.36-1.14(6H，m)，1.19(6H，s)，0.97(3H，s)，0.74(3H，s)，0.25(9H，s)，0.09(9H，s)

(20S)-1,25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol

841mg (1 packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; (1R 473mmol); 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi BuLi that also dropwise add 0.88mL (1.41mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that adds 369mg (0.585mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours, and removed the dry ice in the cooling bath then, make this solution in 1 hour, be warming up to-40 ℃.Mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 560mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 8mL.At room temperature stirred this reactant mixture 8 hours.Add the solution of 1M tetrabutylammonium in oxolane of new a collection of 7mL, and stirred this mixture 40 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (2 times) obtain 327mg (92%) product, be the white foam shape.

c＝0.43，EtOH

UVλmax(EtOH)：243.67nm(ε36197)，252.00nm(ε41649)，261.83nm(ε28455)

¹H NMR(CDCl ₃)：6.31(1H，d，J＝11.2Hz)，6.11(1H，ddd，J＝12.4，9.3，5.7Hz)，5.84(1H，d，J＝10.7Hz)，5.48(1H，d，J＝11.7Hz)，4.12(1H，br s)，4.05(1H，br s)，2.86-2.72(3H，m)，2.50-2.46(2H，m)，2.24-2.18(2H，m)，2.08-1.94(3H，m)，1.88-1.22(18H，m)，1.22(6H，s)，1.06-0.91(2H，m)，0.97(3H，s)，0.65(3H，s)

MS HRES value of calculation: C ₃₂H ₄₈F ₆O ₄[M+Na] ⁺633.3349

Measured value: [M+Na] ⁺633.3348

Embodiment 11

(20S)-and 1 α-fluoro-25-hydroxyl-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(20S)-1 α-fluoro-25-hydroxyl-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 712mg (1.513mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.90mL (1.44mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that dropwise adds 320mg (0.507mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.This mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 6 hours 30 minutes.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (1: 1 and 2: 1) carries out purification as mobile phase.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 300mg (95%) product, be the white foam shape.

c＝0.55，EtOH

UVλmax(EtOH)：207.67nm(ε20792)，242.33nm(ε17972)，270.00nm(ε18053)

¹H NMR(CDCl ₃)：6.40(1H，d，J＝11.1Hz)，6.11(1H，ddd，J＝12.4，9.5，6.0Hz)，6.02(1H，d，J＝11.1Hz)，5.49(1H，d，J＝12.1Hz)，5.39(1H，s)，5.14(1H，ddd，J＝49.5，7.2，4.2Hz)，5.10(1H，s)，4.23(1H，br s)，2.87-2.80(2H，m)，2.62(1H，br d，J＝12.1Hz)，2.48-2.43(1H，m)，2.31(1H，dd，J＝12.9，7.5Hz)，2.22-2.14(1H，m)，2.06-1.97(3H，m)，1.70-1.12(16H，m)，1.22(3H，s)，1.21(3H，m)，1.05-0.91(2H，m)，0.97(3H，s)，0.65(3H，s)

MS HRES value of calculation: C ₃₃H ₄₇F ₇O ₃[M+Na] ⁺647.3305

Measured value: [M+Na] ⁺647.3304

Embodiment 12

(20S)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(3E, 6S)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-glycol

To the solution of 1M lithium aluminium hydride reduction in oxolane that stirring rod is installed and has the 4.0mL (4.0mmol) that packs in the 25mL round-bottomed flask of condenser of nitrogen purging.This mixture is cooled to 0 ℃ and the slow 216mg (4.00mmol) of adding Feldalat NM, (6S)-1 that adds 300mg (0.617mmol) then, 1,1-three fluoro-6-([(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2, the solution of 10-glycol in the 4.0mL oxolane.80 ℃ of this reactant mixtures are stirred 5 hours postcooling to 0 ℃.The 2N NaOH and the 20.0mL ether that add 1.0mL water, 1.0mL.At room temperature stir this mixture 30 minutes, and added the MgSO of 2.2g ₄And this mixture of restir 15 minutes.Filter this suspension and evaporating solvent.With the oily residue through chromatography at pillar (100cm ³And 30cm ³) going up and use dichloromethane: ethyl acetate (4: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 279mg (93%) product, are water white oil.

¹H NMR(CDCl ₃)：6.32(1H，dt，J＝15.7，7.8Hz)，5.59(1H，15.7Hz)，4.09(1H，br s)，2.29(2H，d，J＝7.6Hz)，2.01(1H，br d，J＝3.3Hz)，1.86-1-75(2H，m)，1.63-1.04(18H，m)，1.21(6H，s)，1.09(3H，s)，0.98(3H，s)

¹³C NMR(CDCl ₃)：137.07，119.81，71.52，69.54，69.57，57.20，52.53，44.16，43.50，42.29，41.43，40.10，40.04，33.39，29.33，29.29，23.01，22.17，21.69，17.86，17.51，16.58

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 6S of 274mg (0.561mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3E)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-two pure and mild 10mL dichloromethane.Add 704mg (1.871mmol) pyridinium dichromate and 740mg kieselguhr and at room temperature stirred this mixture 2 hours.With this reactant mixture at silica gel (100cm ³) use dichloromethane on the post: ethyl acetate (4: 1) is filtered as mobile phase.The flow point merging and the evaporation that will comprise product obtain the 253mg yellow oil.This product need not be further purified and be directly used in next step.

(20S)-1, the 25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

(the 1S of 1.765g (3.028mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 10.0mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 1.8mL (2.88mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 253mg (0.520mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours (last 0.5 hour at-20 ℃), remove cooling bath then and in this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up and use hexane: ethyl acetate (4: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (304mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 5mL.At room temperature stirred this reactant mixture 21 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain 176mg (gross production rate of 54%, two step) product, be the white foam shape.

c＝0.33，CHCl ₃

UVλmax(EtOH)：204.50nm(ε17846)，266.17nm(ε16508)

¹H NMR(CDCl ₃)：6.36(1H，d，J＝11.3Hz)，6.32(1H，dt，J＝15.1，7.5Hz)，6.00(1H，d，J＝11.1Hz)，5.59(1H，d，J＝15.8Hz，5.33(1H，s)，4.99(1H，s)，4.53(1H，br s)，4.43(1H，dd，J＝7.7，4.3Hz)，4.25-4.00(1H，m)，2.81(1H，dd，J＝12.1，3.8Hz)，2.59(1H，dd，J＝13.3，2.9Hz)，2.34-2.29(3H，m)，2.05-1.96(3H，m)，1.93-1.87(1H，m)，1.71-1.21(17H，m)，1.21(6H，s)，1.12-1.05(1H，m)，0.95(3H，s)，0.66(3H，s)

¹³C NMR(CDCl ₃)：147.48，142.53，136.92，133.05，124.83，122.39(q，J＝284.7Hz)，119.76，117.58，117.49，111，71，71.61，70.73，66.90，57.39，56.62，46.79，45.18，43.99，42.83，42.48，41.29，40.13，40.04，29.62，29.28，28.98，23.50，23.06，22.24，21.90，17.74，15.11

MS HRES value of calculation: C ₃₃H ₄₈F ₆O ₄[M+Na] ⁺645.3349

Measured value: [M+Na] ⁺645.3346

Embodiment 13

(20S)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 1R of 577mg (1.186mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone and 20mL dichloromethane.1-(TMS) imidazoles that dropwise adds 1.5mL (10.2mmol).At room temperature stirred this mixture 5 hours 30 minutes.Add the 150mL ethyl acetate and use this mixture of 50mL water washing three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 710mg (95%) product, are water white oil.

¹H NMR(CDCl ₃)：6.21(1H，dt，J＝15.1，7.2Hz)，5.56(1H，d，J＝15.4Hz)，1.22-1.19(1H，m)，2.32-1.06(2H，m)，2.27(2H，d，J＝7.0Hz)，2.06-1.52(9H，m)，1.34-1.08(6H，m)，1.20(3H，s)，1.19(3H，s)，0.96(3H，s)，0.73(3H，s)，0.22(9H，s)，0.10(9H，s)

(20S)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol

836mg (1 packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; (1R 464mmol); 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi BuLi that also dropwise add 0.89mL (1.42mmol).At-70 ℃ of (1R that stirred the gained dark red solution 20 minutes and added 360mg (0.571mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 5 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.In this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 440mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 26 hours.The solution of 1M tetrabutylammonium in oxolane that adds new a collection of 2.5mL, and this mixture of restir 6 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (2 times) obtain 303mg (87%) product, be the white foam shape.

{[α]}_{D}^{26} = + 41.8

c＝0.44，EtOH

UVλmax(EtOH)：244nm(ε27480)，252nm(ε32212)，262nm(ε21694)

¹H NMR(CDCl ₃)：6.33(1H，dt，J＝15.6，7.8Hz)，6.29(1H，d，J＝9.0Hz)，5.83(1H，d，J＝11.1Hz)，5.58(1H，d，J＝15.6Hz)，4.12-4.09(1H，m)，4.05-4.02(1H，m)，2.79-2.71(2H，m)，2.46(1H，dd，J＝13.2，3.0Hz)，2.29(2H，d，J＝7.5Hz)，2.20(2H，dd，J＝13.3，7.1Hz)，2.04-1.75(7H，m)，1.68-1.46(9H，m)，1.41-1.21(6H，m)，1.21(6H，s)，1.12-1.05(1H，m)，0.95(3H，s)，0.65(3H，s)

¹³C NMR(CDCl ₃)：142.40，136.79，131.25，123.64，122.4(q，J＝286.96Hz)，119.83，115.76，71.59，67.42，67.18，57.33，56.56，46.64，44.52，44.04，42.40，42.02，41.24，40.10，40.01，37.13，29.54，29.26，28.83，23.39，23.07，22.25，21.87，17.79，15.17

MS HRES value of calculation: C ₃₂H ₄₈F ₆O ₄[M+Na] ⁺633.3349

Measured value: [M+Na] ⁺633.3349

Embodiment 14

(20S)-and 1 α-fluoro-25-hydroxyl-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(20S)-1 α-fluoro-25-hydroxyl-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 521mg (1.107mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.69mL (1.10mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that dropwise adds 324mg (0.514mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.In this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 8mL.At room temperature stirred this reactant mixture 9 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (1: 1) is as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 305mg (95%) product, be the white foam shape.

{[α]}_{D}^{26} = + 29.3

c＝0.43，EtOH

UVλmax(EtOH)：210nm(ε13484)，243nm(ε13340)，271nm(ε13609)

¹H NMR(CDCl ₃)：6.39(1H，d，J＝11.3Hz)，6.32(1H，dt，J＝15.6，7.6Hz)，6.01(1H，d，J＝11.3Hz)，5.58(1H，d，J＝15.8Hz)，2.39(1H，s)，5.13(1H，ddd，J＝49.9，6.3，3.8Hz)，5.09(1H，s)，4.21(1H，br s)，2.81(1H，dd，J＝11.8，3.5Hz)，2.61(1H，dd，J＝13.2，3.2Hz)，2.32-2.28(3H，m)，2.23-2.15(1H，m)，2.04-1.93(3H，m)，1.70-1.48(9H，m)，1.41-1.21(8H，m)，1.21(6H，s)，1.12-1.05(1H，m)，0.95(3H，s)，0.65(3H，s)

¹³C NMR(CDCl ₃)：142.95(d，J＝16.0Hz)，136.84，131.54，125.42，122.42(q，J＝286.9Hz)，119.78，117.53，114.96(d，J＝10.0Hz)，71.74，66.56(d，J＝6.0Hz)，57.35，56.61，46.82，44.91，44.04，42.40，41.29，40.69(d，J＝20.6Hz)，40.10，39.98，29.47，29.20，29.01，23.47，23.07，22.22，21.82，17.79，15.13

MS HRES value of calculation: C ₃₃H ₄₇F ₇O ₃[M+Na] ⁺647.3305

Measured value: [M+Na] ⁺647.3302

Embodiment 15

(20R)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol is synthetic

(3R)-and 3-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-7-hydroxyl-3,7-dimethyl-octanal

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1.558g (7.228mmol) pyridinium chlorochromate, 1.60g kieselguhr and 20mL dichloromethane.(the 3R)-3-[(1R that dropwise adds 1.440g (3.267mmol), 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-3,7-dimethyl-octane-1, the solution of 7-glycol in the 10mL dichloromethane, and at room temperature stirred this mixture 2 hours 50 minutes.With this reactant mixture at silica gel (75cm ³) and kieselguhr (2cm) post on filter, with dichloromethane, dichloromethane: ethyl acetate (4: 1) is as mobile phase.The flow point merging and the evaporation that will comprise product obtain the 1.298g yellow oil.This product need not be further purified and be directly used in next step.

(6R)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2,6-dimethyl-ninth of the ten Heavenly Stems-8-alkynes-2-alcohol

(3R)-3-[(1R of 1.298g (2.958mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-7-hydroxyl-3,7-dimethyl-octanal and 30mL methanol.1-diazo-2-oxo-the propyl group that adds 1.137g (5.916mmol))-the phosphonic acids dimethyl esters in 3mL methanol solution and the gained mixture is cooled to 0 ℃ in ice bath.Add 1.140g (8.248mmol) potassium carbonate and also this reactant mixture was stirred in ice bath 30 minutes, at room temperature stirred then 2 hours 50 minutes.Add 100mL water and use this mixture of 80mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (200cm ³) going up and use hexane: ethyl acetate (7: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 1.151g (81%) product, are water white oil.

c＝0.54，CHCl ₃

¹H NMR(CDCl ₃)：3.99(1H，br s)，2.16-2.07(2H，m)，2.00-1.97(1H，m)，1.92(1H，t，J＝2.6Hz)，1.84-1.74(1H，m)，1.67-1.64(1H，m)，1.58-1.22(16H，m)，1.22(6H，s)，1.04(3H，s)，0.99(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

MS HRES value of calculation: C ₂₇H ₅₀O ₂Si [M+Na] ⁺457.3472

Measured value: [M+Na] ⁺457.3473

(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-1-[(1R)-1,5-dimethyl-1-Propargyl-5-TMS oxygen base-hexyl]-7a-methyl-octahydro-indenes

(6R)-6-[(1R of 1.151g (2.647mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-2, the 6-dimethyl-ninth of the ten Heavenly Stems-pure and mild 20mL dichloromethane of 8-alkynes-2-.1-(TMS) imidazoles that dropwise adds 2.0mL (13.63mmol).At room temperature stirred this mixture 1 hour.Add 100mL water, use this mixture of 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate (25: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 1.260g (94%) product, are water white oil.

c＝0.46，CHCl ₃

¹H NMR(CDCl ₃)：3.98(1H，br s)，2.12-2.08(2H，m)，20.5-1.95(2H，m)，1.92-1.90(1H，m)，1.83-1.21(16H，m)，1.21(6H，s)，1.04(3H，s)，0.98(3H，s)，0.88(9H，s)，0.11(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹³C NMR(CDCl ₃)：83.00，74.07，69.70，69.50，56.63，53.03，45.66，43.74，41.35，39.59，39.45，34.38，29.99，29.60，25.85，22.81，22.43，22.06，18.56，18.05，17.76，16.49，2.65，-4.77，-5.13

MS HRES value of calculation: C ₃₀H ₅₈O ₂Si ₂[M+Na] ⁺529.3867

Measured value: [M+Na] ⁺529.3868

(6R)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three fluoro-6,10-dimethyl-2-Trifluoromethyl-1 0-TMS oxygen base-11-3-alkynes-2-alcohol

To stirring rod being installed, having (the 1R of 1.252g (2.470mmol) that pack in the 50mL two neck round-bottomed flasks of the Clarkson joint of rubber septum and funnel (band cooling bath), 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-1-[(1R)-1,5-dimethyl-1-Propargyl-5-TMS oxygen base-hexyl]-7a-methyl-octahydro-indenes and 25mL oxolane.Funnel is linked to each other with the container that Hexafluoro acetone is housed and cool off (acetone, dry ice).This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 2.4mL (3.84mmol).Add Hexafluoro acetone (valve open of this container three times) after 30 minutes.Stir this reactant 2 hours at-70 ℃, add the 5.0mL saturated ammonium chloride solution then.

Dissolve this mixture and use 80mL ethyl acetate extraction three times by adding the 100mL saturated ammonium chloride solution, use Na ₂SO ₄Dry also evaporation.Residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate (10: 1) separates twice as mobile phase, obtains the mixture of 1.711g product and polymer (from Hexafluoro acetone).

(6R)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2,10-glycol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into thick (about 2.470mmol) (6R)-6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three fluoro-6, the solution of 1M tetrabutylammonium in oxolane of 10-dimethyl-2-Trifluoromethyl-1 0-TMS oxygen base-pure and mild 15.0mL of 11-3-alkynes-2-(15.0mmol).Stirred this reactant mixture 96 hours at 70 ℃.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (200cm ³And 75cm ³) go up and use hexane: ethyl acetate (2: 1) eluting purification.The flow point merging and the evaporation that will comprise product obtain 979mg (81%) product, are water white oil.

c＝0.48，CHCl ₃

¹H NMR(CDCl ₃)：4.08(1H，br s)，2.24(1H，AB，J＝17.2Hz)，2.17(1H，AB，J＝17.2Hz)，2.05-2.02(1H，m)，1.85-1.76(2H，m)，1.66-1.20(18H，m)，1.26(3H，s)，1.25(3H，s)，1.07(3H，s)，1.01(3H，s)

MS HRES value of calculation: C ₂₄H ₃₆F ₆O ₃[M+Na] ⁺509.2461

Measured value: [M+Na] ⁺509.2463

(1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-own-3-alkynyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into (6R)-1 of 291mg (0.598mmol), 1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2,10-two pure and mild 10mL dichloromethane.Add 700mg (1.861mmol) pyridinium dichromate and 720mg kieselguhr and at room temperature stirred this mixture 3 hours.With this reactant mixture at silica gel (75cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate (4: 1,3: 1) is filtered.The flow point merging and the evaporation that will comprise product obtain 271mg (94%) product, are yellow oil.

(20R)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol

(the 1S of 2.118g (3.634mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 2.2mL (3.52mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 271mg (0.559mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-own-3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stir this reactant mixture 5 hours at-78 ℃, remove cooling bath then and in this mixture, pour the 100mL saturated ammonium chloride solution into, use 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (4: 1) is as mobile phase eluting purification.The flow point that will comprise impurity through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (5: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (250mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 5mL.At room temperature stirred this reactant mixture 18 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain 194mg (56%) product, be the white foam shape.

c＝0.38，EtOH

UVλmax(EtOH)：212.33nm(ε14113)，265.00nm(ε15960)

¹H NMR(D6-DMSO)：8.93(1H，s)，6.18(1H，d，J＝11.3Hz)，5.96(1H，d，J＝11.3Hz)，5.22(1H，s)，4.86(1H，d，J＝4.83Hz)，4.75(1H，s)，4.54(1H，d，J＝3.63Hz)，4.20-4.15(1H，m)，4.06(1H，s)，3.98(1H，br s)，2.77(1H，d，J＝13.7Hz)，2.40-2.33(1H，m)，2.27-2.14(3H，m)，2.00-1.90(2H，m)，1.82-1.78(2H，m)，1.64-1.54(5H，m)，1.47-1.18(10H，m)，1.05(3H，s)，1.05(3H，s)，0.95(3H，s)，0.59(3H，s)

¹³C NMR(D6-DMSO)：149.38，139.51，135.94，122.32，121.47(q，J＝287.5Hz)，117.99，109.77，89.53，70.58，68.72，68.35，65.06，56.02，55.91，46.06，44.85，44.65，43.11，29.30，29.03，28.78，28.32，23.05，22.40，21.90，21.52，18.27，14.29

MS HRES value of calculation: C ₃₃H ₄₆F ₆O ₄[M+Na] ⁺643.3192

Measured value: [M+Na] ⁺643.3190

Embodiment 16

(20R)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-19-falls-cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-alkynyl]-octahydro-indenes-4-ketone

(the 1R of 399mg (0.823mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone and 8.0mL dichloromethane.1-(TMS) imidazoles that dropwise adds 0.9mL (6.2mmol).At room temperature stirred this mixture 4 hours.Add the 150mL hexane and use this mixture of 50mL water washing three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate (5: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 492mg (95%) product, are grease.

(20R)-1,25-dihydroxy-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-19-falls-cholecalciferol

(the 1R of 490mg (0.858mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.53mL (0.848mmol).At-70 ℃ of (1R that stirred the gained dark red solution 30 minutes and added 249mg (0.396mmol), 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4.5 hours, and removed the dry ice in the cooling bath then, this solution was heated to-55 ℃ in 1 hour.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 349mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 63 hours.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use hexane: oxolane (1: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product 207mg (86%), are white solid.

{[α]}_{D}^{30} = + 44.7

c＝0.51，EtOH

UV λmax(EtOH)：242nm(ε30834)

¹H NMR(DMSO-D6)：8.96(1H，s)，6.08(1H，d，J＝10.9Hz)，5.78(1H，d，J＝11.3Hz)，4.48(1H，d，J＝4.3Hz)，4.38(1H，d，J＝4.1Hz)，4.07(1H，s)，3.91-3.85(1H，m)，3.84-3.77(1H，m)，2.74(1H，d，J＝13.6Hz)，2.43(1H，dd，J＝13.4，3.4Hz)，2.28-2.20(3H，m)，2.07-1.93(4H，m)，1.84-1.79(1H，m)，1.69-1.21(16H，m)，1.06(3H，s)，1.06(3H，s)，0.97(3H，s)，0.60(3H，s)

¹³C NMR (D6-DMSO): 139.09,134.88,121.60 (q, J=286.0Hz), 120.90,116.56,89.61,70.64,70.45 (septet, J=33.3Hz), 68.77,65.57,65.30,56.00,55.92,45.93,44.66,44.59,42.22,36.95,29.27,29.02,28.78,28.14,22.87,22.38,21.93,21.40,18.24,14.35

MS HRES value of calculation: C ₃₂H ₄₆F ₆O ₄[M+Na] ⁺631.3192

Measured value: [M+Na] ⁺631.3195

Embodiment 17

(20R)-1 α-fluoro-25-hydroxyl-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol synthetic

(20R)-1 α-fluoro-25-hydroxyl-20-(5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-alkynyls)-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 460mg (0.977mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.61mL (0.976mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that dropwise adds 240mg (0.382mmol), 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4.5 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1.5 hours.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 239mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 8mL.At room temperature stirred this reactant mixture 17 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (1: 2 and 1: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 196mg (82%) product, be the white foam shape.

{[α]}_{D}^{30} = + 24.4

c＝0.45，EtOH

UVλmax(EtOH)：241nm(ε17260)，273nm(ε16624)

¹H NMR(DMSO-D6)：8.95(1H，s)，6.37(1H，d，J＝11.5Hz)，5.93(1H，d，J＝11.1Hz)，5.39(1H，s)，5.14(1H，br d，J＝47.1Hz)，4.99(1H，d，J＝1.9Hz)，4.86(1H，d，J＝4.3Hz)，4.07(1H，s)，3.94-3.87(1H，m)，2.83-2.80(1H，m)，2.28-2.05(4H，m)，2.00-1.93(2H，m)，1.83-1.21(17H，m)，1.06(3H，s)，1.06(3H，s)，0.96(3H，s)，0.59(3H，s)

¹³C NMR (D6-DMSO): 143.27 (d, J=16.7Hz), 141.62,133.20,124.14,121.59 (q, J=286.0Hz), 117.49,115.34 (d, J=9.8Hz), 92.05 (d, J=166.9Hz), 89.60,70.64,70.44 (septet, J=32.6Hz), 68.77,64.55 (d, J=4.5Hz), 55.99,55.92,46.15,44.83,44.65,40.68 (d, J=20.5Hz), 40.05,39.79,39.41,29.27,29.02,28.76,28.30,22.95,22.33,21.87,21.39,18.24,14.28

MS HRES value of calculation: C ₃₃H ₄₅F ₇O ₃[M+Na] ⁺645.3149

Measured value: [M+Na] ⁺645.3155

Embodiment 18

(20)-1,25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol (8) synthetic

(3Z, 6R)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-glycol

In a 25mL round-bottomed flask, pack into (6R)-1,1 of 340mg (0.699mmol), 1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2, the 5%Pd/CaCO of 10-glycol, 100mg ₃, 8.0mL hexane, 3.3mL ethyl acetate and the solution (with 3.1mL ethanol and 168 μ l quinoline preparation) of 0.32mL quinoline in ethanol.This reaction substrate is carried out hydrogenation at ambient temperature in hydrogen-pressure.This reaction is monitored (hexane: ethyl acetate 2: 1) by thin layer chromatography.After-filtration removed catalyst and evaporating solvent in 7 hours.Residue is at silica gel (50cm ³) go up and use hexane: ethyl acetate (2: 1) eluting purification.The flow point merging and the evaporation that will comprise product obtain 320mg (94%) product, are water white oil.

¹H NMR(CDCl ₃)：6.12-6.03(1H，m)，5.46(1H，d，J＝13.2Hz)，4.08(1H，br s)，2.46-2.40(2H，m)，2.06-1.95(1H，m)，1.86-1.76(2H，m)，1.66-1.20(18H，m)，1.21(6H，s)，1.09(3H，s)，0.99(3H，s)

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 1R of 315mg (0.645mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3Z)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-two pure and mild 12.0mL dichloromethane.Add 780mg (1.861mmol) pyridinium dichromate and at room temperature stirred this mixture 3 hours.

With this reactant mixture at silica gel (100cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate (4: 1,3: 1) is filtered.The flow point merging and the evaporation that will comprise product obtain 305mg (97%) product, are yellow oil.

c＝0.37，CHCl ₃

¹H NMR(CDCl ₃)：6.07(1H，dt，J＝12.4，7.3Hz)，5.49(1H，d，J＝11.9Hz)，4.33(1H，br s)，2.52(1H，dd，J＝16.2，7.7Hz)，2.45-2.38(2H，m)，2.31-2.10(3H，m)，2.06-1.98(1H，m)，1.96-1.81(1H，m)，1.79-1.35(12H，m)，1.23(6H，s)，0.99(3H，s)，0.75(3H，s)

MS HRES value of calculation: C ₂₄H ₃₆F ₆O ₃[M+Na] ⁺509.2461

Measured value: [M+Na] ⁺509.2463

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 1R of 295mg (0.606mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone and 8.0mL dichloromethane.1-(TMS) imidazoles that dropwise adds 0.7mL (4.8mmol).At room temperature stirred this mixture 3 hours.Add 100mL water and use this mixture of 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 362mg (95%) product, are water white oil.

¹H NMR(CDCl ₃)：6.02-5.94(1H，m)，5.42(1H，d，J＝11.0Hz)，2.50-2.40(2H，m)，2.35-2.14(4H，m)，2.06-1.55(7H，m)，1.43-1.14(7H，m)，1.21(6H，s)，0.96(3H，s)，0.74(3H，s)，0.24(9H，s)，0.10(9H，s)

(20)-1, the 25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

(the 1S of 757mg (1.299mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 0.8mL (1.28mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 360mg (0.571mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stir this reactant mixture 4 hours 30 minutes (last 0.5 hour at-30 ℃), remove cooling bath then and in this mixture, pour 50mL ethyl acetate and 100mL saline into.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (15: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise the chemical compound of product and the single deprotection of part obtain water white oil (430mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 6 hours 40 minutes.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain 278mg (gross production rate of 78%, two step) product, be the white foam shape.

c＝0.51，EtOH

UVλmax(EtOH)：212.67nm(ε15573)，265.17nm(ε17296)

¹H NMR(D6-DMSO)：7.97(1H，s)，6.18(1H，d，J＝11.3Hz)，6.09(1H，dt，J＝12.1，6.3Hz)，5.96(1H，d，J＝11.3Hz)，5.42(1H，d，J＝12.1Hz)，5.22(1H，s)，4.86(1H，d，J＝4.8Hz)，4.75(1H，s)，4.54(1H，d，J＝3.6Hz)，4.20-4.36(1H，m)，4.04(1H，s)，4.00-3.96(1H，m)，2.77(1H，br d，J＝11.1Hz)，2.49-2.39(2H，m)，2.3591H，d，J＝11.9Hz)，2.16(1H，dd，J＝13.4，5.3Hz)，2.00-1.86(2H，m)，1.83-1.77(1H，m)，1.70-1.15(16H，m)，1.04(3H，s)，1.04(3H，s)，0.90(3H，s)，0.60(3H，s)

¹³C NMR(D6-DMSO)：149.40，139.75，139.21，135.81，122.94(q，J＝287.7Hz)，122.36，117.87，117.15，109.75，68.72，68.34，65.08，56.56，55.98，46.15，44.85，44.69，43.11，40.35，38.85，36.04，29.43，29.12，28.34，23.13，22.79，21.83，21.50，17.96，14.55

MS HRES value of calculation: C ₃₃H ₄₈F ₆O ₄[M+Na] ⁺645.3349

Measured value: [M+Na] ⁺645.3337

Embodiment 19

(20)-1,25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol synthetic

(20)-1,25-dihydroxy-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol

804mg (1 packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; (1R 408mmol); 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLi BuLi that also dropwise add 0.88mL (1.41mmol).At-70 ℃ of (1R that stirred the gained dark red solution 25 minutes and added 441mg (0.699mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 6 hours at-70 ℃.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (25: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain grease (about 615mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 15mL.At room temperature stirred this reactant mixture 18 hours.The 1M tetrabutylammonium that adds new a collection of 5mL solution and this mixture of restir 48 hours in oxolane.Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use ethyl acetate: hexane (1: 2,1: 1 and 3: 1) and ethyl acetate are as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (2 times) obtain 395mg (92%) product, be the white foam shape.

c＝0.50，EtOH

UV λmax(EtOH)：244nm(ε35888)，252nm(ε41722)，262nm(ε28261)

¹H NMR(DMSO-D6)：7.99(1H，s)，6.14-6.08(1H，m)，6.08(1H，d，J＝12.4Hz)，5.78(1H，d，J＝11.3Hz)，5.44(1H，d，J＝12.4Hz)，4.48(1H，d，J＝4.1Hz)，4.38(1H，d，J＝4.1Hz)，4.05(1H，s)，3.89-3.84(1H，m)，3.83-3.77(1H，m)，2.73(1H，d，J＝13.2Hz)，2.49-2.41(2H，m)，2.26(1H，d，J＝10.4Hz)，2.07-1.96(4H，m)，1.72-1.20(18H，m)，1.05(3H，s)，1.05(3H，s)，0.91(3H，s)，0.61(3H，s)

¹³C NMR (D6-DMSO): 139.41,139.34,134.75,123.07 (q, J=288.2Hz), 120.95,117.26,116.46,76.83 (septet, J=28.1Hz), 68.77,65.59,65.31,56.56,55.98,46.01,44.71,44.61,42.22,40.35,39.01,38.78,36.96,36.07,29.44,29.11,22.97,22.78,21.88,21.38,17.94,14.64

MS HRES value of calculation: C ₃₂H ₄₈F ₆O ₄[M+Na] ⁺633.3349

Measured value: [M+Na] ⁺633.3357

Embodiment 20

(20)-and 1 α-fluoro-25-hydroxyl-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(20)-1 α-fluoro-25-hydroxyl-20-[(2Z)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 673mg (1.430mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.89mL (1.42mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, (the 1R that dropwise adds 320mg (0.507mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 2 hours.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (25: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain grease (568mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 17 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With this oily residue through twice column chromatography purification: 50cm ³(lucifuge) uses ethyl acetate: hexane (1: 1) is as mobile phase, and 50cm ³(lucifuge) uses hexane: ethyl acetate (2: 1 and 1: 1) is as mobile phase.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 365mg (81%) product, be the white foam shape.

c＝0.49，EtOH

UVλmax(EtOH)：210nm(ε15393)，243nm(ε15181)，270nm(ε15115)

¹H NMR(DMSO-D6)：7.99(1H，s)，6.36(1H，d，J＝11.3Hz)，6.10(1H，dt，J＝12.2，6.3Hz)，5.93(1H，d，J＝11.3Hz)，5.43(1H，d，J＝12.2Hz)，5.39(1H，s)，5.14(1H，br d，J＝47.5Hz)，4.99(1H，d，J＝1.7Hz)，4.85(1H，d，J＝4.3Hz)，4.05(1H，s)，3.94-3.88(1H，m)，2.81(1H，d，J＝13.2Hz)，2.47-2.41(2H，m)，2.16-2.05(2H，m)，2.01-1.96(2H，m)，1.83-1.18(17H，m)，1.05(3H，s)，1.05(3H，s)，0.90(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 143.30 (d, J=16.7Hz), 141.89,139.35,133.08,124.18,123.05 (q, J=288.2Hz), 117.37,117.24,115.26 (d, J=9.1Hz), 92.02 (d, J=167.6Hz), 76.84 (septet, J=28.1Hz), 68.76,64.53,56.55,55.95,46.25,44.82,44.70,40.68 (d, J=20.5Hz), 40.29,38.95,38.77,36.06,29.41,29.12,28.32,23.03,22.71,21.81,21.37,17.93,14.55

MS HRES value of calculation: C ₃₃H ₄₇F ₇O ₃[M+Na] ⁺647.3305

Measured value: [M+Na] ⁺647.3297

Embodiment 21

(20R)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(3E, 6R)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-glycol

Stirring rod is installed and has the solution of 1M lithium aluminium hydride reduction in oxolane of the 4.5mL (4.5mmol) that packs in the 25mL round-bottomed flask of condenser of nitrogen purging and this mixture is cooled to 0 ℃ to one.Slowly add 243mg (4.50mmol) Feldalat NM, (the 3E that adds reaction substrate 337mg (0.693mmol) then, 6R)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkynes-2, the solution of 10-glycol in the 5mL oxolane.Stir 6 hours 30 minutes postcooling to 0 of these reactant mixtures ℃ at 80 ℃.The 2N NaOH and the 20mL ether that add 1mL water, 1mL.At room temperature stir this mixture 30 minutes and added the MgSO of 2.2g ₄, and this mixture of restir 15 minutes.Filter this suspension and evaporating solvent.With the oily residue through chromatography at pillar (100cm ³) going up and use dichloromethane: ethyl acetate (4: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 330mg (97%) product, are water white oil.

¹H NMR(CDCl ₃)：6.28(1H，dt，J＝15.7，7.3Hz)，5.59(1H，d，J＝15.4Hz)，6.12(1H，br s)，2.12(2H，d，J＝7.7Hz)，2.06-1.98(1H，m)，1.85-1.74(2H，m)，1.68-1.16(18H，m)，1.22(6H，s)，1.08(3H，s)，0.98(3H，s)

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 3E of 330mg (0.675mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 6Z)-1,1,1-three fluoro-6-[(1R, 3aR, 4S, 7aR)-and 4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6,10-dimethyl-2-trifluoromethyl-11-3-alkene-2,10-two pure and mild 10mL dichloromethane.Add 920mg (2.445mmol) pyridinium dichromate and at room temperature stirred this mixture 7 hours.

With this reactant mixture at silica gel (60cm ³) use dichloromethane on the post: ethyl acetate (4: 1) is filtered as mobile phase.The flow point merging and the evaporation that will comprise product obtain 302mg (92%) product, are water white oil.

c＝0.46，CHCl ₃

¹H NMR(CDCl ₃)：6.30(1H，dt，J＝15.6，7.7Hz)，5.60(1H，d，J＝15.6Hz)，2.40(1H，dd，J＝11.1，7.3Hz)，2.30-2.14(6H，m)，2.06-1.98(1H，m)，1.96-1.81(1H，m)，1.78-1.30(13H，m)，1.24(3H，s)，1.23(3H，s)，0.98(3H，s)，0.74(3H，s)

¹³C NMR(CDCl ₃)：212.12，136.27，120.28，71.45，62.27，57.44，50.69，44.28，42.02，40.76，40.17，39.69，39.65，29.34，29.23，23.98，22.66，22.24，18.67，18.19，15.47

MS HRES value of calculation: C ₂₄H ₃₆F ₆O ₃[M+Na] ⁺509.2461

Measured value: [M+Na] ⁺509.2463

(1R, 3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(the 1R of 292mg (0.600mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-5-hydroxyl-1-(4-hydroxy-4-methyl-amyl group)-1-methyl-5-trifluoromethyls-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone and 8mL dichloromethane.1-(TMS) imidazoles that dropwise adds 0.7mL (4.8mmol).At room temperature stirred this mixture 2 hours.Add 100mL water and use this mixture of 50mL ethyl acetate extraction three times, use Na ₂SO ₄Dry also evaporation.

With the oily residue through chromatography at pillar (60cm ³) going up and use hexane: ethyl acetate (10: 1,4: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 360mg (95%) product, are water white oil.

(20R)-1, the 25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

(the 1S of 760mg (1.304mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 10mL oxolane.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in oxolane that also dropwise add 0.8mL (1.28mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 358mg (0.567mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 4 hours (last 0.5 hour under-20 ℃), remove cooling bath then, this mixture is poured in 50mL ethyl acetate and the 100mL saline.With 50mL ethyl acetate extraction water section three times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and some single deprotections obtain water white oil (440mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 21 hours.

Dissolve this mixture and use 50mL water by adding the 150mL ethyl acetate: saline (1: 1) and the extraction of 50mL saline six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 305mg (gross production rate of two steps is 86%) product, are colorless solid.

c＝0.44，EtOH

UVλmax(EtOH)：212.76nm(ε15453)，265.03(ε17341)

¹H NMR(D6-DMSO)：8.04(1H，s)，6.28(1H，dt，J＝15.5，7.6Hz)，6.18(1H，d，J＝11.1Hz)，5.97(1H，d，J＝11.1Hz)，5.61(1H，d，J＝15.5Hz)，5.22(1H，s)，4.75(1H，s)，4.19-4.16(1H，m)，3.98(1H，br s)，2.77(1H，d，13.9Hz)，2.35(1H，d，J＝11.7Hz)，2.16(1H，dd，J＝13.6，5.3Hz)，2.07(2H，d，J＝7.3Hz)，1.99-1.90(2H，m)，1.81-1.78(1H，m)，1.64-1.55(6H，m)，1.48-1.17(12H，m)，1.05(6H，s)，0.90(3H，s)，0.84(1H，s)，0.61(3H，s)

¹³C NMR(D6-DMSO)：149.34，139.65，136.40，135.82，122.60(q，J＝287.7Hz)，122.32，119.80，117.90，109.76，68.68，68.36，65.04，56.35，56.00，46.18，44.85，44.64，43.09，41.05，40.42，29.34，29.12，28.31，23.08，22.47，21.79，21.58，17.91，14.57

MS HRES value of calculation: C ₃₃H ₄₈F ₆O ₄[M+Na] ⁺645.3349

Measured value: [M+Na] ⁺645.3355

Embodiment 22

(20R)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol synthetic

(20R)-1,25-dihydroxy-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-19-falls-cholecalciferol

(the 1R of 493mg (0.864mmol) packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.54mL (0.86mmol).At-70 ℃ of (1R that stirred the gained dark red solution 25 minutes and added 240mg (0.380mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 7 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (about 380mg), and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 10mL.At room temperature stirred this reactant mixture 50 hours.Dissolve this mixture and, use Na by adding the 150mL ethyl acetate with 50mL water extraction six times ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up and use hexane: oxolane (1: 1,1: 2 and 1: 2+10% methanol) as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product 181mg (78%), are colorless solid.

{[α]}_{D}^{30} = + 52.8

c＝0.50，EtOH

UVλmax(EtOH)：241nm(ε26823)

¹H NMR(DMSO-D6)：8.05(1H，s)，6.29(1H，dt，J＝15.3，7.7Hz)，6.07(1H，d，J＝11.1Hz)，5.78(1H，d，J＝11.1Hz)，5.63(1H，d，J＝15.3Hz)，4.48(1H，s)，4.38(1H，s)，4.06(1H，s)，3.87(1H，s)，3.80(1H，s)，2.74(1H，d，J＝14.5Hz)，2.43(1H，dd，J＝13.0，3.4Hz)，2.28-2.25(1H，m)，2.10-1.91(6H，m)，1.62-1.27(17H，m)，1.06(3H，s)，1.06(3H，s)，0.91(3H，s)，0.61(3H，s)

¹³C NMR (D6-DMSO): 139.25,136.60,134.79,122.73 (q, J=286.8Hz), 120.93,119.96,116.50,75.55 (septet, J=28.8Hz), 68.74,65.57,65.29,56.38,56.00,46.05,44.67,44.60,42.22,41.07,40.43,36.95,29.35,29.12,28.14,22.92,22.47,21.83,21.47,17.90,14.66

MS HRES value of calculation: C ₃₂H ₄₈F ₆O ₄[M+Na] ⁺633.3349

Measured value: [M+Na] ⁺633.3350

Embodiment 23

(20R)-and 1 α-fluoro-25-hydroxyl-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol synthetic

(20R)-1 α-fluoro-25-hydroxyl-20-[(2E)-5,5,5-three fluoro-4-hydroxyl-4-trifluoromethyl-penta-2-thiazolinyls]-cholecalciferol

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 439mg (0.933mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 8mL oxolane.This reactant mixture is cooled to-70 ℃ of 1.6M n-BuLis that also dropwise add 0.58mL (0.93mmol).At-70 ℃ of (1R that stirred the gained dark red solution 25 minutes and dropwise added 238mg (0.377mmol), 3aR, 4S, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(4-methyl-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-solution of 4-ketone in the 1.5mL oxolane.Stirred this reactant mixture 6 hours, and removed the dry ice in the cooling bath then, this solution was heated to-40 ℃ in 1 hour.This mixture is poured in ethyl acetate (50ml) and the saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (10: 1) is as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1M tetrabutylammonium in oxolane of 8mL.At room temperature stirred this reactant mixture 15 hours.

Dissolve this mixture and, use Na by adding the 150mL ethyl acetate with 50mL water extraction six times ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (1: 2 and 1: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this product be dissolved in methyl acetate and the evaporation (2 times) obtain 195mg (83%) product, be the white foam shape.

{[α]}_{D}^{26} = + 29.3

c＝0.43，EtOH

UVλmax(EtOH)：243nm(ε11639)，273nm(ε10871)

¹H NMR(DMSO-D6)：8.05(1H，s)，6.37(1H，d，J＝11.3Hz)，6.28(1H，dt，J＝15.3，7.6Hz)，5.93(1H，d，J＝11.3Hz)，5.62(1H，d，J＝15.6Hz)，5.39(1H，s)，5.14(1H，br d，J＝47.7Hz)，4.99(1H，d，J＝1.5Hz)，4.87(1H，br s)，4.06(1H，brs)，3.93-3.88(1H，m)，2.81(1H，d，J＝11.9Hz)，2.16-2.06(4H，m)，1.99-1.91(2H，m)，1.82-1.26(17H，m)，1.06(3H，s)，1.06(3H，s)，0.90(3H，s)，0.60(3H，s)

¹³C NMR (D6-DMSO): 143.26 (d, J=17.5Hz), 141.80,136.57,133.12,124.17,122.73 (q, J=285.2Hz), 119.96,117.42,115.37 (d, J=9.9Hz), 92.06 (d, J=166.9Hz), 75.54 (septet, J=28.8Hz), 68.74,64.55 (d, J=4.5Hz), 56.38,55.99,46.28,44.84,44.67,41.07,40.69 (d, J=20.5Hz), 40.39,29.34,29.14,28.31,22.99,22.42,21.76,21.47,17.90,14.58

MS HRES value of calculation: C ₃₃H ₄₇F ₇O ₃[M+Na] ⁺647.3305

Measured value: [M+Na] ⁺647.3313

Embodiment 24

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol synthetic

8-(tert-butyl group-dimethyl-silanyloxy base)-6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three deuterium generation-6-methyl-2-three deuterium acute pyogenic infection of nails base-octane-2-alcohol

At one stirring rod is installed, has 7-(tert-butyl group-dimethyl-silanyloxy the base)-5-[(1R that packs in the 250mL round-bottomed flask of Clarkson joint of rubber septum, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-5-methyl-cognac oil (18.770g, 32.987mmol) and ether (150mL).This solution of cooling also dropwise adds 1.0M methyl-d in ice-water bath ₃-magnesium iodide is at ether (100.0mL, 100.0mmol) solution in.At room temperature stirred this mixture after adding 3 hours, cooling once more in ice bath then.Dropwise add saturated ammonium chloride solution (10ml).Add saturated ammonium chloride solution (100ml) and dissolve the gained precipitation.With ether (3 * 100ml) aqueous layer extracted.With the organic layer drying (Na that merges ₂SO ₄) and evaporation.This oily residue is used for next step.

(3S)-3-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1, the 7-glycol and

(3R)-and 3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1,7-glycol

8-(tert-butyl group-dimethyl-silanyloxy base)-6-[(1R packs in a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1,1-three deuterium generation-6-methyl-2-three deuterium acute pyogenic infection of nails base-octane-2-alcohol (about 32.9mmol), oxolane (60ml) and tetrabutylammonium (45.0ml, 1M/ oxolane).At room temperature stirred this reactant mixture 2.5 hours.Dissolve this mixture and water by adding ethyl acetate (150ml): saline (1: 1,100ml) and saline (50ml) washing six times, drying (Na ₂SO ₄) and evaporation.This oily residue separates (VersaPak post, 80 * 150mm and 40 * 150mm, hexane/ethyl acetate 1: 1) 10 times on chromatographic column, obtain product (12.72g, 87%):

(3S)-and 3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1,7-glycol (6.69g, low polar epimer)

{[α]}_{D}^{31} = + 16.0

(c＝0.60，EtOH)

¹H NMR(CDCl ₃)：3.99(1H，br s)，3.69-3.63(2H，m)，2.02(1H，br d，J＝12.2Hz)，1.82-1.48(7H，m)，1.40-1.09(14H，m)，1.06(3H，s)，0.95(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

MS HRES value of calculation: C ₂₆H ₄₆D ₆O ₃Si [M+Na] ⁺469.3954

Measured value: [M+Na] ⁺469.3956

(3R)-and 3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1,7-glycol (6.03g, stronger polar epimer)

{[α]}_{D}^{31} = + 20.0

(c＝0.54，EtOH)

¹H NMR(CDCl ₃)：3.99-3.97(1H，m)，3.66-3.62(2H，m)，1.98(1H，br d，J＝12.8Hz)，1.84-1.73(1H，m)，1.67-1.51(6H，m)，1.42-1.16(14H，m)，1.05(3H，s)，0.95(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

MS HRES value of calculation: C ₂₆H ₄₆D ₆O ₃Si [M+Na] ⁺469.3954

Measured value: [M+Na] ⁺469.3957

(3S)-and 3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-7-hydroxy-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanals

In a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium chlorochromate (2.90g, 13.45mmol), kieselguhr (4.0g) and dichloromethane (60mL).Dropwise add (3S)-3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1, (4.00g, 8.95mmol) solution in dichloromethane (5mL) also at room temperature stirred this mixture 2 hours 40 minutes to the 7-glycol.

With this reactant mixture at silica gel (200cm ³) and kieselguhr (2cm) post on dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain grease (3.61g, 91%).Product is directly used in next step without purification.

(6S)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1, three deuterium acute pyogenic infection of nails base-ninth of the ten Heavenly Stems of 1-three deuterium generation-6-methyl-2--8-alkynes-2-alcohol

(3S)-3-[(1R packs in a 100mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-7-hydroxy-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanals (3.61g, 8.116mmol) and methanol (65ml).Add 1-diazo-2-oxo-propyl group)-the phosphonic acids dimethyl esters (3.00g, the 15.62mmol) solution in methanol (3mL), and the gained mixture cooled off in ice bath.(3.00g 21.74mmol) also stirred this reactant mixture 30 minutes in ice bath, at room temperature stirred then 4 hours to add potassium carbonate.Also (4 * 80ml) extract this mixture, dry (Na with ethyl acetate to add entry (100ml) ₂SO ₄) and evaporation.

With the oily residue through chromatography at pillar (300cm ³) going up and to use hexane: ethyl acetate-9: 1 and 8: 1 are as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (3.131g, 87.5%).

{[α]}_{D}^{26} = + 17.6

(c＝0.83，EtOH)

¹H NMR(CDCl ₃)：3.98(1H，br d，J＝2.13Hz)，2.28(1H，AB，J＝17.3Hz)，2.26(1H，AB，J＝17.3Hz)，1.96-1.91(2H，m)，1.84-1.73(1H，m)，1.67-1.48(5H，m)，1.43-1.24(12H，m)，1.04(3H，s)，1.00(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹³C NMR (CDCl ₃): 83.06,76.41 (septet, J=29.6Hz), 69.84,69.55,56.54,52.87,44.66,43.68,41.27,40.16,39.28,34.32,28.76,25.87,22.76,22.69,22.17,18.10,17.76,16.78 ,-4.69 ,-5.05

MS HRES value of calculation: C ₂₇H ₄₄D ₆O ₂Si [M+Na] ⁺463.3849

Measured value: [M+Na] ⁺463.3848

(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-[(1S)-6,6,6-three deuterium generation-1-methyl isophthalic acids-(Propargyl)-5-three deuterium acute pyogenic infection of nails bases-5-TMS oxygen base-hexyl]-octahydro-indenes

(6S)-6-[(1R packs in a 100mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1, three deuterium acute pyogenic infection of nails base-ninth of the ten Heavenly Stems of 1-three deuterium generation-6-methyl-2--8-alkynes-2-alcohol (3.100g, 7.033mmol) and dichloromethane (30mL).Dropwise add 1-(TMS) imidazoles (3.0mL, 20.45mmol).At room temperature stirred this mixture 1 hour 45 minutes.Also (3 * 100ml) extract this mixture, dry (Na with ethyl acetate to add entry (100ml) ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (125cm ³) going up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (3.36g, 93%).

{[α]}_{D}^{26} = + 15.4

(c＝0.52，CHCl ₃)

¹H NMR(CDCl ₃)：3.99(1H，br s)，2.27(2H，br s)，2.00-1.93(2H，m)，1.84-1.73(1H，m)，1.65(1H，d，J＝14.3Hz)，1.59-1.49(3H，m)，1.42-1.20(12H，m)，1.05(3H，s)，1.00(3H，s)，0.88(9H，s)，0.10(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹³C NMR (CDCl ₃): 83.18,76.66 (septet, J=28.8Hz), 69.74,69.58,56.62,52.91,45.38,43.67,41.27,40.07,39.28,34.34,28.77,25.88,22.76,22.16,18.13,18.11,17.77,16.76,2.74 ,-4.69 ,-5.05

MS HRES value of calculation: C ₃₀H ₅₂D ₆O ₂Si ₂[M+Na] ⁺535.4244

Measured value: [M+Na] ⁺535.4246

(6S)-and 6-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-Trifluoromethyl-1 0-TMS oxygen base-11-3-alkynes-2-alcohol

At one stirring rod is installed, has (the 1R that packs in the 100mL two neck round-bottomed flasks of the Clarkson joint of rubber septum and funnel (band cooling bath), 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-[(1S)-6,6,6-three deuterium generation-1-methyl isophthalic acids-(Propargyl)-5-three deuterium acute pyogenic infection of nails bases-5-TMS oxygen base-hexyl]-octahydro-indenes (3.330g, 6.491mmol) and oxolane (40mL).Funnel is linked to each other with the container that Hexafluoro acetone is housed and cool off (acetone, dry ice).With this reactant mixture be cooled to-70 ℃ and dropwise add n-BuLi (6.10mL, 9.76mmol).Add Hexafluoro acetone (valve open of container three times) after 30 minutes.Stir this reactant at-70 ℃ and add saturated ammonium chloride solution (5ml) after 2 hours.Adding saturated ammonium chloride solution (100ml) dissolves this mixture and uses ethyl acetate (3 * 60ml) extractions, dry (Na ₂SO ₄) and evaporation.With residue through twice column chromatography purification (300cm ³, hexane: ethyl acetate-25: 1 and 20: 1) and obtain the mixture (4.33g) of product and polymer (from Hexafluoro acetone).Product is directly used in next reaction without purification.

(6S)-and 6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2,10-glycol

(6S)-6-[(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-Trifluoromethyl-1 0-TMS oxygen base-11-3-alkynes-2-alcohol (about 3.3mmol) and tetrabutylammonium (25ml, 1M/ oxolane) also stirred these reactants 113 hours at 70 ℃.Dissolve this mixture and water-saline (1: 1,50ml) extraction was six times, dry (Na by adding ethyl acetate (150ml) ₂SO ₄) and evaporation.

With product crystallization from hexane (1.996g, 62%).

{[α]}_{D}^{31} = - 6.3

(c＝0.46，EtOH)

¹H NMR(DMSO-D6)：8.92(1H，s)，4.21(1H，d，J＝3.0Hz)，4.04(1H，s)，3.87(1H，s)，2.37(2H，s)，1.89(1H，d，J＝11.5Hz)，1.76-1.48(6H，m)，1.33-1.11(11H，m)，1.02(3H，s)，0.96(3H，m)

¹³C NMR (DMSO-D6): 121.47 (q, J=286.8Hz), 89.70,70.71,70.40 (septet, J=31.9Hz), 68.41,66.86,56.24,52.37,44.45,42.96,40.44,39.38,33.70,28.14,22.43,22.01,21.68,17.73,17.46,16.32

MS HRES value of calculation: C ₂₄H ₃₀D ₆F ₆O ₃[M+Na] ⁺515.2837

Measured value: [M+Na] ⁺515.2838

(1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-own-3-alkynyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.51g, 4.01mmol) and dichloromethane (20mL).Dropwise add (6S)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2,10-glycol (712mg, 1.445mmol) solution in dichloromethane (5mL), and at room temperature stirred this mixture 2 hours 45 minutes.

With this reactant mixture at silica gel (50cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain grease.This product is directly used in next reaction without purification.

(1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-alkynyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-the 5-trifluoromethyl-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (about 1.445mmol) and dichloromethane (10mL).Dropwise add 1-(TMS) imidazoles (2.00mL, 13.63mmol).At room temperature stirred this mixture 2 hours.(3 * 50ml) wash this mixture, dry (Na to add ethyl acetate (150ml) and water ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate-5: 1 is as mobile phase eluting purification.This product unstable on silica gel (obtaining the chemical compound (246mg) of single protection).The flow point merging and the evaporation that will comprise product obtain product, are water white oil (585mg, 64%).

¹H NMR(CDCl ₃)：2.44-2.37(3H，m)，2.32-2.16(2H，m)，2.11-1.99(2H，m)，1.95-1.84(2H，m)，1.81-1.52(5H，m)，1.38-1.20(6H，m)，1.03(3H，s)，0.74(3H，s)，0.28(9H，s)，0.10(9H，s)

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (532mg, 0.913mmol) and oxolane (8mL).This reactant mixture is cooled to-78 ℃ also dropwise adds n-BuLi (0.57mL, 0.912mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, and dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (281mg, 0.443mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 5 hours (temperature rose to-55 ℃ from-70 in the end one hour).Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil.This oily residue is used for next reaction.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 25 hours.Dissolve this mixture and water (50mL) and saline (50ml) by adding ethyl acetate (150ml) and wash 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product ( ¹H, ¹³Impurity (Bu is arranged CNMR) ₃N).This material is at chromatographic column (70cm ³, lucifuge) go up and use hexane: ethyl acetate 1: 1 and ethyl acetate are as mobile phase eluting purification.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (191mg, 69%).

{[α]}_{D}^{25} = + 3.6

(c＝0.44，EtOH)

UVλmax(EtOH)：213nm(ε15402)，264nm(ε17663)

¹H NMR(DMSO-D6)：8.95(1H，br s)，6.18(1H，d，J＝11.1Hz)，5.97(1H，d，J＝11.1Hz)，5.23(1H，d，J＝1.1Hz)，4.88(1H，d，J＝3.4Hz)，4.75(1H，d，J＝1.7Hz)，4.56(1H，s)，4.19(1H，br s)，4.06(1H，br s)，3.99(1H，br s)，2.78(1H，d，J＝12.2Hz)，2.45-2.29(2H，m)，2.17(1H，dd，J＝13.2，5.4Hz)，1.96-1.91(2H，m)，1.84-1.73(2H，m)，1.65-1.18(17H，m)，0.96(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 149.40,139.51,135.95,122.33,121.49 (q, J=286.0Hz), 118.02,109.77,89.59,70.84,70.43 (septet, J=31.9Hz), 68.42,68.37,65.09,56.36,55.94,45.97,44.87,44.43,43.12,39.98,39.85,39.43,28.35,28.27,23.11,22.51,22.02,21.42,17.77,14.44

MS HRES value of calculation: C ₃₃H ₄₀D ₆F ₆O ₄[M+Na] ⁺649.3569

Measured value: [M+Na] ⁺649.3572

Embodiment 25

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (562mg, 0.984mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.61mL, 0.98mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (296mg, 0.466mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 4 hours 40 minutes (temperature rose to-55 ℃ from-70 in the end one hour).Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil (380mg).In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 49 hours.Dissolve this mixture and water (50mL) and saline (50ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.

With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil.This product ( ¹H, ¹³Impurity (Bu is arranged CNMR) ₃N).This material is at chromatographic column (60cm ³, lucifuge) go up and to use hexane: ethyl acetate 2: 1 and ethyl acetate are as twice of mobile phase purification.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (251mg, 87%).

{[α]}_{D}^{22} = + 33.5

(c＝0.48，EtOH)

UVλmax(EtOH)：243nm(ε29859)，252nm(ε34930)，262nm(ε23522)

¹H NMR(DMSO-D6)：8.94(1H，s)，6.07(1H，d，J＝11.0Hz)，5.78(1H，d，J＝11.0Hz)，4.48(1H，d，J＝4.0Hz)，4.38(1H，d，J＝4.0Hz)，4.04(1H，s)，3.92-3.76(2H，m)，2.77(1H，br d，J＝11.0Hz)，2.49-2.25(2H，m)，2.05-1.95(4H，m)，1.76-1.20(19H，m)，0.97(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 138.95,134.73,121.50 (q, J=286.0Hz), 120.80,116.47,89.59,70.84,70.44 (septet, J=31.9Hz), 68.43,65.57,65.45,65.28,56.37,55.91,45.82,44.59,44.45,42.23,40.01,39.43,36.98,28.29,28.19,22.98,22.54,22.08,21.33,17.78,14.55

MS HRES value of calculation: C ₃₂H ₄₀D ₆F ₆O ₄[M+Na] ⁺637.3569

Measured value: [M+Na] ⁺637.3570

Embodiment 26

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (500mg, 1.062mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ and also dropwise adds n-BuLi (0.66mL, 1.06mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (269mg, 0.424mmol) solution in oxolane (1.5mL).Stir this reactant mixture 5h (temperature rose to-55 ℃ from-70 in the end a hour).Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (100ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil.This oily residue is used for next reaction.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).Stirred this mixture 6 hours.Dissolve this mixture and water (50mL) and saline (50ml) by adding ethyl acetate (150ml) and wash 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-1: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product ( ¹H, ¹³Impurity (Bu is arranged C NMR) ₃N).This material is at chromatographic column (60cm ³, lucifuge) to go up and to use hexane: ethyl acetate 2: 1 and 1: 1 are as the mobile phase purification.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (229mg, 86%).

{[α]}_{D}^{25} = + 20.9

(c＝0.45，EtOH)

UVλmax(EtOH)：211nm(ε15893)，243nm(ε16109)，270nm(ε16096)

¹H NMR(DMSO-D6)：8.93(1H，s)，6.36(1H，d，J＝11.1Hz)，5.93(1H，d，J＝11.3Hz)，5.38(1H，s)，5.14(1H，ddd，J＝49.6，3.4，2.0Hz)，4.98(1H，d，J＝1.5Hz)，4.86(1H，d，J＝4.3Hz)，4.05(1H，s)，3,94-3.88(1H，m)，2.81(1H，d，J＝13.2Hz)，2.44-2.35(2H，m)，2.16-2.08(2H，m)，1.98-1.93(2H，m)，1.84-1.17(17H，m)，0.95(3H，s)，0.59(3H，s)

¹³C NMR (DMSO-D6): 143.15 (d, J=16.7Hz), 141.49,133.06,124.03,121.49 (q, J=286.0Hz), 117.40,115.18 (d, J=9.9Hz), 91.97 (d, J=166.9Hz), 89.61,70.85,70.44 (septet, J=31.9Hz), 68.43,64.55 (d, J=4.6Hz), 56.37,55.91,46.06,44.84,44.44,40.70 (d, J=20.5Hz), 39.97,39.81,39.43,28.37,28.26,23.06,22.52,22.02,21.32,17.77,14.48

MS HRES value of calculation: C ₃₃H ₃₉D ₆F ₇O ₃[M+Na] ⁺651.3526

Measured value: [M+Na] ⁺651.3528

Embodiment 27

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol synthetic

(6S, 3Z)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkene-2,10-glycol

(6S)-6-[(1R packs in a 50ml round-bottomed flask, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2, and the 10-glycol (722mg, 1.466mmol), Pd/CaCO ₃(180mg, 5%), hexane (16.8mL), ethyl acetate (6.8mL) and the quinoline solution (0.65mL is with ethanol (3.1ml) and quinoline (168 μ l) preparation) in ethanol.

Reaction substrate is carried out hydrogenation at ambient temperature in hydrogen-pressure.This reaction by thin layer chromatography monitoring (dichloromethane: ethyl acetate 4: 1,3x).

After 5 hours 10 minutes, (using kieselguhr) filtration catalizer and evaporating solvent.

Residue is at silica gel (50cm ³) go up and use dichloromethane: 4: 1 eluting purification of ethyl acetate.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (720mg, 99%).

{[α]}_{D}^{31} = + 3.3

(c＝0.49，EtOH)

¹H NMR(CDCl ₃)：6.14-6.05(1H，m)，5.48(1H，d，J＝12.8Hz)，4.08(1H，s)，2.83(1H，dd，J＝15.6，9.0Hz)，2.48-2.40(1H，m)，2.00(1H，d，J＝11.4Hz)，1.85-1.73(2H，m)，1.64-1.24(18H，m)，1.08(3H，s)，0.99(3H，s)

¹³C NMR(CDCl ₃)：140.29，117.60，71.72，69.91，56.94，52.76，44.28，43.62，41.36，40.39，39.79，36.97，33.53，22.78，22.40，21.88，17.81，13.73

MS HRES value of calculation: C ₂₄H ₃₂D ₆F ₆O ₃[M+Na] ⁺517.2994

Measured value: [M+Na] ⁺517.2997

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.50g, 3.99mmol) and dichloromethane (15mL).Dropwise add (6S, 3Z)-and 6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkene-2, the 10-glycol (710mg, the 1.436mmol) solution in dichloromethane (5mL), and at room temperature stirred this mixture 6 hours.

With this reactant mixture at silicagel column (50cm ³) going up with dichloromethane, dichloromethane: ethyl acetate was filtered in 4: 1 and 3: 1.The flow point merging and the evaporation that will comprise product obtain grease (694mg, 98%).

¹H NMR(CDCl ₃)：6.10(1H，m)，5.52(1H，d，J＝12.4Hz)，5.07(1H，br s)，2.92(1H，dd，J＝16.1，9.9Hz)，2.48-2.38(2H，m)，2.91-1.25(18H，m)，0.99(3H，s)，0.74(3H，s)

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-the 5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (690mg, 1.401mmol) and dichloromethane (8mL).Dropwise add 1-(TMS) imidazoles (1.8mL, 12.3mmol).At room temperature stirred this mixture 1.5 hours.Add ethyl acetate (150ml) and water (50ml) and wash this mixture three times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (854mg, 96%).

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (539mg, 0.925mmol) and oxolane (8ml).With this reactant mixture be cooled to-78 ℃ and dropwise add n-BuLi (0.58mL, 0.93mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (270mg, 0.424mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 4 hours 30 minutes, and removed cooling bath then and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (60ml).Extract this water section three times with ethyl acetate (50ml), dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil (350mg).

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into described grease and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 24 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (232mg, 87%).

{[α]}_{D}^{27} = - 5.4

(c＝0.46，EtOH)

UVλmax(EtOH)：213nm(ε15177)，266nm(ε18553)

¹H NMR(DMSO-D6)：8.02(1H，s)，6.19(1H，d，J＝11.3Hz)，6.11(1H，dt，J＝12.1，6.3Hz)，5.98(1H，d，J＝11.1Hz)，5.42(1H，d，J＝12.4Hz)，5.23(1H，s)，4.87(1H，d，J＝4.7Hz)，4.76(1H，s)，4.55(1H，d，J＝3.4Hz)，4.20-4.17(1H，m)，4.03(1H，s)，3.98(1H，br s)，2.82-2.75(2H，m)，2.45(1H，dd，J＝16.6，4.9Hz)，2.36(1H，d，J＝11.9Hz)，2.17(1H，dd，J＝13.04，5.3Hz)，2.04-1.95(2H，m)，1.84-1.79(1H，m)，1.73-1.54(6H，m)，1.48-1.31(4H，m)，1.22-1.17(6H，m)，0.86(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 149.41,139.79,139.46,135.80,122.95 (q, J=186.7Hz), 122.37,117.85,117.01,109.75,76.76 (septet, J=28.9Hz), 68.41,68.37,65.10,56.45,56.02,51.21,46.09,44.87,44.55,43.12,40.31,39.37,38.74,35.68,28.37,23.21,22.88,21.81,21.55,17.60,14.58

MS HRES value of calculation: C ₃₃H ₄₂D ₆F ₆O ₄[M+Na] ⁺651.3725

Measured value: [M+Na] ⁺651.3728

Embodiment 28

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (541mg, 0.948mmol) and oxolane (8ml).With this reactant mixture be cooled to-78 ℃ and dropwise add n-BuLi (0.59mL, 0.94mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (286mg, 0.449mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 4 hours 10 minutes, and removed cooling bath then and also this mixture is poured in ethyl acetate (50ml) and the saturated ammonium chloride solution (60ml).Extract this water section three times with ethyl acetate (50ml), dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil (390mg).

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into described grease and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 30 hours.Adding ethyl acetate (150ml) is dissolved this mixture and water and saline (30ml+20ml) and is extracted 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up and carry out purification as mobile phase with ethyl acetate.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (264mg, 95%).

{[α]}_{D}^{26} = + 32.0

(c＝0.47，EtOH)

UVλmax(EtOH)：244nm(ε31469)，252nm(ε36060)，262nm(ε24658)

¹H NMR(DMSO-D6)：8.02(1H，s)，6.14-6.08(1H，m)，6.08(1H，d，J＝11.9Hz)，5.78(1H，d，J＝11.1Hz)，5.43(1H，d，J＝12.2Hz)，4.49(1H，d，J＝4.1Hz)，4.39(1H，d，J＝4.1Hz)，4.04(1H，s)，3.88-3.78(2H，m)，2.82-2.72(2H，m)，2.48-2.42(2H，m)，2.31-2.25(1H，m)，2.07-1.90(4H，m)，1.73-1.18(17H，m)，0.87(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 139.45,139.19,134.57,122.94 (q, J=286.8Hz), 120.84,117.02,116.29,76.75 (septet, J=28.8Hz), 68.41,65.55,65.27,56.43,55.98,45.94,44.60,44.55,42.23,40.32,39.38,38.74,36.97,35.69,28.21,23.07,22.89,21.85,21.44,17.59,14.69

MS HRES value of calculation: C ₃₂H ₄₂D ₆F ₆O ₄[M+Na] ⁺639.3725

Measured value: [M+Na] ⁺639.3724

Embodiment 29

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (462mg, 0.982mmol) and oxolane (8ml).This reactant mixture is cooled to-78 ℃ also dropwise adds n-BuLi (0.61mL, 0.98mmol)).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (267mg, 0.419mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 5 hours, and removed cooling bath then and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (60ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 5 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (1: 1) is carried out purification as mobile phase.

Product comprises some impurity, and (VersaPak, 40 * 75mm) upward use hexane: ethyl acetate (1: 1) is as mobile phase eluting purification in chromatographic column once more with it.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (244mg, 92%).

{[α]}_{D}^{26} = + 11.8

(c＝0.51，EtOH)

UV λmax(EtOH)：244nm(ε15004)，270nm(ε15084)

¹H NMR(DMSO-D6)：8.02(1H，s)，6.36(1H，d，J＝11.3Hz)，6.14-6.07(1H，m)，5.39(1H，d，J＝11.3Hz)，5.42(1H，d，J＝11.9Hz)，5.39(1H，s)，5.14(1H，brd，J＝49.7Hz)，4.99(1H，d，J＝1.7Hz)，4.86(1H，d，J＝4.3Hz)，4.03(1H，s)，3.93-3.88(1H，m)，2.82-2.74(2H，m)，2.48-2.43(2H，m)，2.17-1.97(4H，m)，1.84-1.55(6H，m)，1.46-1.32(4H，m)，1.29-1.16(7H，m)，0.86(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 143.18 (d, J=16.7Hz), 141.74,139.43,132.93,124.08,122.95 (q, J=286.7Hz), 117.22,117.01,115.08 (d, J=9.1Hz), 91.93 (d, J=166.9Hz), 76.76 (septet, J=28.0Hz), 68.41,64.56,56.43,55.96,46.18,44.82,44.54,40.69 (d, J=20.5Hz), 40.27,38.73,35.68,28.38,23.15,22.85,21.80,21.45,17.59,14.61

MS HRES value of calculation: C ₃₃H ₄₁D ₆F ₇O ₃[M+Na] ⁺653.3682

Measured value: [M+Na] ⁺653.3689

Embodiment 30

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol synthetic

(6S, 3E)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

Stirring rod is installed and has to one and pack lithium aluminium hydride reduction (12.0mL, 12.0mmol, 1M/ oxolane) in the 25mL round-bottomed flask of condenser of nitrogen purging into and this mixture is cooled to 0 ℃.Slowly add Feldalat NM (648mg, 12.0mmol), add (6S)-6-[(1R, 3aR then, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-methyl isophthalic acid 1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2,10-glycol (740mg, 1.502mmol) solution in oxolane (8ml).Stir this reactant mixture 4 hours down at 80 ℃, be cooled to 0 ℃ then.Slowly add saturated ammonium chloride solution (5mL), add saturated ammonium chloride solution (60mL) and 2NHCl (20mL) then.(3 * 50ml) extract this mixture, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at post (50cm ³) going up and use hexane: ethyl acetate-4: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (727mg, 98%).

{[α]}_{D}^{30} = - 0.64

(c＝0.47，EtOH)

¹H NMR(CDCl ₃)：6.32(1H，dt，J＝15.4，7.9)，5.58(1H，d，J＝15.8Hz)，4.09(1H，br s)，2.29(2H，d，J＝8.1Hz)，2.04-1.97(1H，m)，1.84-1.76(2H，m)，1.63-1.18(18H，m)，1.09(3H，s)，0.98(3H，s)

¹³C NMR(CDCl ₃)：137.23，120.09，71.53，69.83，57.36，52.71，44.27，43.69，42.44，41.61，40.22，33.54，23.20，22.36，21.88，18.02，17.70，17.31，16.77

MS HRES value of calculation: C ₂₄H ₃₂D ₆F ₆O ₃[M+Na] ⁺517.2994

Measured value: [M+Na] ⁺517.2994

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.50g, 3.99mmol) and dichloromethane (15mL).Dropwise add (6S, 3E)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkene-2, (730mg, 1.476mmol) solution in dichloromethane (5mL) also at room temperature stirred this mixture 4.5 hours to the 10-glycol.

With this reactant mixture at silica gel (50cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain grease (706mg, 97%).

{[α]}_{D}^{30} = - 20.0

(c＝0.46，EtOH)

¹H NMR(CDCl ₃)：6.33(1H，dt，J＝15.3，7.7Hz)，5.61(1H，d，J＝15.6Hz)，2.43(1H，dd，J＝11.2，7.1Hz)，2.33-2.19(4H，m)，2.17-2.12(1H，m)，2.06-2.00(1H，m)，1.95-1.84((1H，m)，1.80-1.54(7H，m)，1.40-1.20(5H，m)，1.15-1.09(1H，m)，0.98(3H，s)，0.75(3H，s)

¹³C NMR(CDCl ₃)：211.74，136.54，119.96，71.25，62.22，57.49，50.59，43.80，42.54，40.85，39.97，39.80，24.04，23.03，22.10，18.67，17.72，15.71

MS HRES value of calculation: C ₂₄H ₃₀D ₆F ₆O ₃[M+Na] ⁺515.2837

Measured value: [M+Na] ⁺515.2837

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-the 5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (698mg, 1.417mmol) and dichloromethane (8mL).Dropwise add 1-(TMS) imidazoles (1.8mL, 12.3mmol).At room temperature stirred this mixture 2 hours.(4 * 50ml) wash this mixture, dry (Na to add ethyl acetate (150ml) and water ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (60cm ³) going up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (871mg, 96%).

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (531mg, 0.911mmol) and oxolane (8ml).This reactant mixture is cooled to-78 ℃ also dropwise adds n-BuLi (0.57mL, 0.91mmol)).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (260mg, 0.408mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 5 hours 30 minutes, and removed cooling bath then and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (60ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and oxolane (5mL).The adding tetrabutylammonium (2.10g, 6.66mmol).This mixture of restir 6 hours also adds tetrabutylammonium (5mL, 1M/ oxolane).This reactant of restir 15 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (186mg, 73%).

{[α]}_{D}^{30} = + 4.5

(c＝0.44，EtOH)

UV λmax(EtOH)：213nm(ε13978)，265nm(ε16276)

¹H NMR(CDCl ₃)：6.37(1H，d，J＝11.1Hz)，6.31(1H，dd，J＝15.6，7.9Hz)，6.00(1H，d，J＝11.1Hz)，5.59(1H，d，J＝15.6Hz)，5.33(1H，s)，4.99(1H，s)，4.43(1H，br s)，4.23(1H，br s)，2.81(1H，dd，J＝12.2，3.4Hz)，2.59(1H，br d，J＝10.5Hz)，2.34-2.29(3H，m)，2.06-1.98(3H，m)，1.93-1.87(1H，m)，1.76-1.18(18H，m)，1.12-1.06(1H，m)，0.95(3H，s)，0.66(3H，s)

¹³C NMR (DMSO-D6): 149.41,139.75,136.73,135.85,122.63 (q, J=285.2Hz), 122.39,119.72,117.94,109.79,75.51 (septet, J=29.6Hz), 68.41,65.11,56.54,56.02,46.13,44.87,44.43,43.11,41.20,40.48,28.37,23.14,22.90,21.72,21.52,17.56,14.70

MS HRES value of calculation: C ₃₃H ₄₂D ₆F ₆O ₄[M+Na] ⁺651.3725

Measured value: [M+Na] ⁺651.3727

Embodiment 31

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (546mg, 0.956mmol) and oxolane (8ml).This reactant mixture is cooled to-78 ℃ also dropwise adds n-BuLi (0.60mL, 0.96mmol)).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (295mg, 0.463mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 5 hours 30 minutes, and removed cooling bath then and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (60ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 42 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (280mg, 98%).

{[α]}_{D}^{30} = + 41.1

(c＝0.46，EtOH)

UVλmax(EtOH)：244nm(ε32355)，252nm(ε37697)，262nm(ε25353)

¹H NMR(DMSO-D6)：8.04(1H，s)，6.32(1H，dt，J＝15.6，7.7Hz)，6.07(1H，d，J＝11.1Hz)，5.78(1H，d，J＝11.1Hz)，5.63(1H，d，J＝15.3Hz)，4.50(1H，d，J＝3.4Hz)，4.39(1H，d，J＝3.4Hz)，4.04(1H，s)，3.88(1H，br s)，3.80(1H，br s)，2.74(1H，br d，J＝13.9Hz)，2.44(1H，dd，J＝13.0，3.0Hz)，2.33-2.21(2H，m)，2.07-1.95(2H，m)，1.69-1.04(17H，m)，0.90(3H，s)，0.62(3H，s)

¹³C NMR (DMSO-D6): 139.13,136.71,134.63,122.44 (q, J=285.2Hz), 120.83,119.71,116.38,75.51 (septet, J=28.9Hz), 68.37,65.57,65.28,56.52,55.97,45.96,44.59,44.44,42.23,41.18,40.48,39.62,39.58,37.00,28.19,22.99,22.91,21.76,21.42,17.55,14.79

MS HRES value of calculation: C ₃₂H ₄₂D ₆F ₆O ₄[M+Na] ⁺639.3725

Measured value: [M+Na] ⁺639.3724

Embodiment 32

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20S-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (473mg, 1.005mmol) and oxolane (8ml).This reactant mixture is cooled to-78 ℃ and also dropwise adds n-BuLi (0.63mL, 1.01mmol)).Stirred the gained dark red solution 20 minutes at-78 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1S, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (271mg, 0.426mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 4.5 hours, and removed cooling bath then and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (60ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (10ml, 1M/ oxolane).This mixture of restir 17 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (1: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (226mg, 84%).

{[α]}_{D}^{28} = + 25.3

(c＝0.45，EtOH)

UVλmax(EtOH)：243nm(ε14182)，269nm(ε14044)

¹H NMR(DMSO-D6)：8.03(1H，s)，6.36(1H，d，J＝10.9Hz)，6.33-6.27(1H，m)，5.93(1H，d，J＝11.1Hz)，5.63(1H，d，J＝15.4Hz)，5.38(1H，s)，5.14(1H，brd，J＝49.7Hz)，4.99(1H，s)，4.86(1H，d，J＝4.3Hz)，4.03(1H，s)，3.94-3.88(1H，m)，2.81(1H，br d，J＝12.4Hz)，2.34-2.20(2H，m)，2.16-2.06(2H，m)，Z2.00-1.95(1H，m)，1.84-1.02(18H，m)，0.89(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 143.17 (d, J=16.7Hz), 141.68,136.70,132.97,124.05,122.62 (q, J=286.7Hz), 119.71,117.29,115.16,91.95 (d, J=166.9Hz), 75.50 (septet, J=28.8Hz), 68.36,64.56,56.51,55.95,46.19,44.83,44.42,41.15,40.69 (d, J=20.5Hz), 40.41,39.61,28.36,23.06,22.88,21.70,21.40,17.54,14.71

MS HRES value of calculation: C ₃₃H ₄₁D ₆F ₇O ₃[M+Na] ⁺653.3682

Measured value: [M+Na] ⁺653.3686

Embodiment 33

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol synthetic

(3R)-and 3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-7-hydroxy-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanals

In a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium chlorochromate (3.858g, 17.898mmol), kieselguhr (3.93g) and dichloromethane (70mL).Dropwise add (3R)-3-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanes-1, (5.00g, 11.190mmol) solution in dichloromethane (10mL) also at room temperature stirred this mixture 3 hours 45 minutes to the 7-glycol.With this reactant mixture through silica gel (250cm ³) and kieselguhr (1cm) post with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain grease (4.42g, 89%).

(6R)-and 6-[(1R, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1, three deuterium acute pyogenic infection of nails base-ninth of the ten Heavenly Stems of 1-three deuterium generation-6-methyl-2--8-alkynes-2-alcohol

(3R)-3-[(1R packs in a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-8,8,8-three deuterium generation-7-hydroxy-3-methyl-7-three deuterium acute pyogenic infection of nails base-octanals (4.42g, 9.937mmol) and methanol (65ml).Add 1-diazo-2-oxo-propyl group)-phosphonic acids dimethyl esters (3.75g, 19.52mmol) solution in methanol (3mL) and the gained mixture cooled off in ice bath.(3.75g 27.13mmol) also stirred this reactant mixture 30 minutes in ice bath, at room temperature stirred then 4 hours to add potassium carbonate.Also (4 * 80ml) extract this mixture, dry (Na with ethyl acetate to add entry (100ml) ₂SO ₄) and evaporation.Residue is through silica gel (50cm ³) use hexane: ethyl acetate-5: 1 is filtered and evaporation.

(the VersaPak post, 80 * 150mm) go up and to use hexanes: ethyl acetate-5: 1 and 4: 1 are as mobile phase eluting purification at pillar through chromatography with the oily residue.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (3.83g, 87%).

¹H NMR(CDCl ₃)：3.99(1H，br s)，2.12-1.92(4H，m)，1.83-1.75(1H，m)，1.68-1.22(17H，m)，1.04(3H，s)，0.99(3H，s)，0.88(9H，s)，0.00(3H，s)，-0.01(3H，s)

¹²C NMR(CDCl ₃)：82.90，70.75，69.67，69.60，60.33，56.61，52.99，44.73，43.71，41.35，39.55，39.51，34.34，29.51，25.83，22.77，22.39，22.03，18.49，18.03，17.73，16.48，14.19，-4.79，-5.14

(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-[(1R)-6,6,6-three deuterium generation-1-methyl isophthalic acids-(Propargyl)-5-three deuterium acute pyogenic infection of nails bases-5-TMS oxygen base-hexyl]-octahydro-indenes

(6R)-6-[(1R packs in a 100mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-and 4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-1,1, three deuterium acute pyogenic infection of nails base-ninth of the ten Heavenly Stems of 1-three deuterium generation-6-methyl-2--8-alkynes-2-alcohol (3.80g, 8.62mmol) and dichloromethane (30mL).Dropwise add 1-(TMS) imidazoles (3.7mL, 25.22mmol).At room temperature stirred this mixture 1 hour 35 minutes.Also (3 * 70ml) extract this mixture, dry (Na with hexane to add entry (100ml) ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (250cm ³) going up and use hexane: ethyl acetate-20: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (4.09g, 93%).

(6R)-and 6-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-6-methyl

isophthalic acid

At one stirring rod is installed, has (the 1R that packs in the 100mL two neck round-bottomed flasks of the Clarkson joint of rubber septum and funnel (band cooling bath), 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl isophthalic acid-[(1R)-6,6,6-three deuterium generation-1-methyl isophthalic acids-(Propargyl)-5-three deuterium acute pyogenic infection of nails bases-5-TMS oxygen base-hexyl]-octahydro-indenes (4.09g, 7.97mmol) and oxolane (50mL).Funnel is linked to each other with the container that Hexafluoro acetone is housed and cool off (acetone, dry ice).This reactant mixture be cooled to-70 ℃ and dropwise add n-BuLi (7.5mL, 12.00mmol).Add Hexafluoro acetone (valve open of this container three times) after 30 minutes.Stir this reactant 2 hours at-70 ℃, add saturated ammonium chloride solution (5ml) then.Saturated ammonium chloride solution (100ml) dissolves this mixture and (3 * 80ml) extract, dry (Na with ethyl acetate by adding ₂SO ₄) and evaporation.Residue is through chromatographic column (300cm ³, hexane: ethyl acetate-20: 1) purification twice, obtains the mixture (5.56g) of product and polymer (from Hexafluoro acetone).Product is directly used in next step without purification.

(6R)-and 6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-methyl

isophthalic acid

One be equipped with stirring rod and rubber septum 100mL two neck round-bottomed flasks in (the 6R)-6-[(1R that packs into, 3aR, 4S, 7aR)-4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-6-methyl

isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-Trifluoromethyl-1 0-TMS oxygen base-11-3-alkynes-2-alcohol (5.56g), acetonitrile (48ml) and oxolane (12ml).With H ₂SiF ₆(35%) solution is divided into small quantities of adding: 5mL, 2mL (after 1 hour 20 minutes), 4mL (after 50 minutes), 5mL (after 1 hour 40 minutes), 5mL (after 1 hour 30 minutes), 5mL (after 16 hours).Gained mixture water (50ml) dilutes and pours in the mixture of ethyl acetate (50ml) and water (50ml) after 5 hours.Collect organic facies and with ethyl acetate (2 * 50ml) aqueous phase extracted again.With the organic layer drying (Na that merges ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (450cm ³) going up and use dichloromethane: ethyl acetate (5: 1) is as mobile phase eluting purification.(the VersaPak post, 40 * 150mm) go up and to use hexanes: ethyl acetate-2: 1 and 1: 1 are as mobile phase eluting purification at pillar with this mixture flow point.The flow point that will comprise product merges and evaporation obtains product (3.303g, two steps totally 84%).

{[α]}_{D}^{30} = + 1.4

(c＝0.59，EtOH)

¹H NMR(CDCl ₃)：4.09(1H，br s)，2.16(1H，AB，J＝17.2Hz)，2.23(1H，AB，J＝17.2Hz)，2.05-2.01(1H，m)，1.85-1.76(2H，m)，1.65-1.21(18H，m)，1.06(3H，s)，1.01(3H，s)

¹³C NMR (CDCl ₃): 121.35 (q, J=286.0Hz), 90.34,72.39,71.06 (septet, J=32.6Hz), 69.48,56.99,52.48,43.51,43.13,40.91,40.39,39.97,33.35,30.05,22.54,22.14,21.92,18.09,17.47,16.10

MS HRES value of calculation: C ₂₄H ₃₀D ₆F ₆O ₃[M+Na] ⁺515.2837

Measured value: [M+Na] ⁺515.2836

(1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-own-3-alkynyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.620g, 4.306mmol) and dichloromethane (15mL).Dropwise add (6R)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-methyl

isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2,10-glycol (783mg, 1.583mmol) solution in dichloromethane (2mL) and DMF (0.5mL), and at room temperature stirred this mixture 5 hours.With this reactant mixture at silica gel (50cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain product, are yellow oil.This oily residue is used for next reaction.

(1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-own-3-alkynyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-the 5-trifluoromethyl-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (about 1.58mmol) and dichloromethane (8mL).Dropwise add 1-(TMS) imidazoles (1.90mL, 12.95mmol).At room temperature stirred this mixture 1.5 hours.(3 * 50ml) wash this mixture, dry (Na to add hexane (150ml) and water ₂SO ₄) and evaporation.

With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate-5: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (918mg, 95%).

{[α]}_{D}^{30} = - 20.8

(c＝0.61，DMSO)

¹H NMR(CDCl ₃)：2.41(1H，dd，J＝11.3，7.2Hz)，2.31-2.12(4H，m)，2.05-1.24(15H，m)，1.00(3H，s)，0.73(3H，s)，0.27(9H，s)，0.10(9H，s)

MS HRES value of calculation: C ₃₀H ₄₄D ₆F ₆O ₃Si ₂[M+Na] ⁺657.3471

Measured value: [M+Na] ⁺657.3467

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (500mg, 0.858mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.53mL, 0.85mmol)).Stirred the gained dark red solution 20 minutes down at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (314mg, 0.495mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 8 hours (in the end one hour rise to-50 ℃ with temperature) from-70.Add saturated ammonium chloride solution (1ml) and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 60ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain grease.

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (10ml, 1M/ oxolane).This mixture of restir 41 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (70cm ³, lucifuge) go up with ethyl acetate as the mobile phase purification.The flow point that will comprise impurity through chromatography at next pillar (70cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (198mg, 64%).

{[α]}_{D}^{28} = + 11.0

(c＝0.50，EtOH)

UVλmax(EtOH)：213nm(ε17873)，264nm(ε20804)

¹H NMR(DMSO-D6)：8.95(1H，s)，6.19(1H，d，J＝11.3Hz)，5.97(1H，d，J＝11.3Hz)，5.22(1H，s)，4.86(1H，d，J＝4.9Hz)，4.75(1H，d，J＝1.9Hz)，4.55(1H，d，J＝3.8Hz)，4.20-4.18(1H，m)，4.04(1H，s)，4.01-3.98(1H，m)，2.78(1H，d，J＝13.6Hz)，2.35(1H，d，J＝13.4Hz)，2.28-2.14(3H，m)，1.99-1.92(2H，m)，1.83-1.78(2H，m)，1.64-1.57(5H，m)，1.47-1.21(10H，m)，0.96(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 149.56,139.66,136.09,122.45,121.61 (q, J=286.7Hz), 118.13,109.87,89.59,70.67,70.46 (septets, J=31.9Hz), 68.48,68.42,65.13,56.05,55.96,46.09,44.88,44.55,43.13,40.12,38.88,28.77,28.31,23.03,22.37,21.89,21.51,18.21,14.25

MS HRES value of calculation: C ₃₃H ₄₀D ₆F ₆O ₄[M+Na] ⁺649.3569

Measured value: [M+Na] ⁺649.3569

Embodiment 34

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (568mg, 0.995mmol) and oxolane (8ml).With this reactant mixture be cooled to-70 ℃ and dropwise add n-BuLi (0.62mL, 0.99mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (306mg, 0.482mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 6 hours, and added saturated ammonium chloride solution (1ml) then and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain grease.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 96 hours.

Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (223mg, 75%).

{[α]}_{D}^{27} = + 45.5

(c＝0.42，EtOH)

UVλmax(EtOH)：244nm(ε36685)，252nm(ε42933)，262nm(ε28904)

¹H NMR(DMSO-D6)：8.95(1H，s)，6.07(1H，d，J＝11.1Hz)，5.78(1H，d，J＝11.1Hz)，4.48(1H，d，J＝4.3Hz)，4.38(1H，d，J＝3.8Hz)，4.04(1H，s)，3.90-3.76(2H，m)，2.74(1H，d，J＝13.4Hz)，2.43(1H，d，J＝14.1Hz)，2.28-2.19(3H，m)，2.07-1.93(3H，m)，1.81(1H，dd，J＝9.6，9.2Hz)，1.68-1.22(17H，m)，0.96(3H，s)，0.59(3H，s)

¹³C NMR(DMSO-D6)：139.10，134.88，121.61(q，J＝286.7Hz)，120.92，116.57，89.60，70.67，68.49，65.60，65.32，56.01，55.94，45.94，44.60，44.55，42.23，39.80，36.96，28.80，28.15，22.89，22.39，21.94，21.42，18.22，14.37

MS HRES value of calculation: C ₃₂H ₄₀D ₆F ₆O ₄[M+Na] ⁺637.3569

Measured value: [M+Na] ⁺637.3565

Embodiment 35

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23-alkynes-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction] (542mg, 1.152mmol) and oxolane (8ml).With this reactant mixture be cooled to-70 ℃ and dropwise add n-BuLi (0.71mL, 1.14mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-alkynyl]-octahydro-indenes-4-ketone (292mg, 0.460mmol) solution in oxolane (1.5mL).Stirred this reactant mixture 7 hours (in the end one hour rise to-50 ℃ with temperature) from-70.Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).With ethyl acetate (3 * 50ml) extraction water parts, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as the mobile phase purification.The flow point merging and the evaporation that will comprise product obtain grease.This oily residue is used for next reaction.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (8ml, 1M/ oxolane).This mixture of restir 48 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-1: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (278mg, 96%).

{[α]}_{D}^{27} = + 26.4

(c＝0.50，EtOH)

UVλmax(EtOH)：210nm(ε14823)，244nm(ε14731)，270nm(ε14798)

¹H NMR(DMSO-D6)：8.95(1H，s)，6.36(1H，d，J＝11.1Hz)，5.93(1H，d，J＝11.3Hz)，5.38(1H，s)，5.14(1H，br d，J＝49.6Hz)，4.98(1H，d，J＝1.9Hz)，4.86(1H，d，J＝4.5Hz)，4.04(1H，s)，3.94-3.87(1H，m)，2.82(1H，d，J＝10.2Hz)，2.27-2.05(4H，m)，2.00-1.93(2H，m)，1.83-1.55(7H，m)，1.48-1.21(10H，m)，0.95(3H，s)，0.58(3H，s)

¹³C NMR (DMSO-D6): 143.31 (d, J=16.7Hz), 141.67,133.23 (d, J=1.5Hz), 124.18,121.64 (q, J=286.0Hz), 117.53,115.37 (d, J=9.2Hz), 92.09 (167.6Hz), 89.59,70.70,70.48 (septet, J=31.9Hz), 68.51,64.61,64.57,56.02,55.96,46.19,44.86,44.56,40.71 (d, J=19.7Hz), 39.82,28.80,28.34,22.98,22.35,21.90,21.43,18.24,14.31

MS HRES value of calculation: C ₃₃H ₃₉D ₆F ₇O ₃[M+Na] ⁺651.3526

Measured value: [M+Na] ⁺651.3530

Embodiment 36

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol synthetic

(6R, 3Z)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

(6R)-6-[(1R packs in a 50ml round-bottomed flask, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2, and the 10-glycol (800mg, 1.624mmol), Pd/CaCO ₃(200mg, 5%), hexane (18.6mL), ethyl acetate (7.6mL) and the quinoline solution (0.72mL is with ethanol (3.1ml) and quinoline (168 μ l) preparation) in ethanol.This reaction substrate is carried out hydrogenation at ambient temperature in hydrogen-pressure.This reaction by thin layer chromatography indicate (dichloromethane: ethyl acetate 4: 1,3 *).After-filtration removed catalyst (silica gel 50cm in 5 hours 10 minutes ³Ethyl acetate 1: 1) and evaporating solvent, hexane:.With product at hexane: crystallization in the ethyl acetate (750mg, 93%).

{[α]}_{D}^{30} = - 2.34

(c＝0.47，EtOH)

¹H NMR(CDCl ₃)：6.07(1H，dt，J＝12.4，7.2Hz)，5.45(1H，d，J＝12.4Hz)，4.08(1H，d，J＝2.1Hz)，2.50-2.39(2H，m)，2.03(1H，d，J＝11.1Hz)，1.88-1.79(2H，m)，1.67-1.22(18H，m)，1.09(3H，s)，0.98(3H，s)

¹³C NMR(CDCl ₃)：139.98，122.83(q，J＝286.7Hz)，117.24，71.45，69.57，56.67，52.55，44.08，43.56，41.21，39.71，39.13，37.19，33.39，22.42，22.15，21.86，17.92，17.54，16.47

MS HRES value of calculation: C ₂₄H ₃₂D ₆F ₆O ₃[M+Na] ⁺517.2994

Measured value: [M+Na] ⁺517.2992

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.520g, 4.040mmol) and dichloromethane (20mL).Dropwise add (6R, 3Z)-and 6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkene-2, the 10-glycol (730mg, the 1.476mmol) solution in dichloromethane (5mL), and at room temperature stirred this mixture 4 hours 20 minutes.

With this reactant mixture through silica gel (50cm ³) post is with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point that will comprise product merges and evaporation.This product is directly used in next step without purification.

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (about 1.47mmol) and dichloromethane (8mL).Dropwise add 1-(TMS) imidazoles (1.80mL, 12.27mmol).At room temperature stirred this mixture 3 hours.Also (3 * 50ml) extract this mixture, dry (Na with ethyl acetate to add entry (50ml) ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (75cm ³) going up and use hexane: ethyl acetate-5: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (766mg, 81%).

¹H NMR(CDCl ₃)：5.98(1H，dt，J＝12.5，6.2Hz)，5.42(1H，d，J＝11.4Hz)，2.49-2.40(2H，m)，2.34-2.15(4H，m)，2.07-1.95(1H，m)，1.93-1.60(6H，m)，1.43-1.19(7H，m)，0.95(3H，s)，0.74(3H，s)，0.24(9H，s)，0.10(9H，s)

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (473mg, 0.811mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.50mL, 0.80mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (280mg, 0.440mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 6 hours (in the end one hour rise to-50 ℃ with temperature) from-70.Add saturated ammonium chloride solution (1ml) and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (100ml).With ethyl acetate (3 * 70ml) extraction water parts, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point that will contain the chemical compound of product and the single deprotection of part merges and evaporation, obtains colorless oil.

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 29 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-1: 2 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (224mg, 81%).

{[α]}_{D}^{29} = + 7.5

(c＝0.48，EtOH)

UV λmax(EtOH)：213nm(ε15024)，265nm(ε17330)

¹H NMR(DMSO-D6)：7.98(1H，s)，6.18(1H，d，J＝11.1Hz)，6.10(1H，dt，J＝12.8，6.4Hz)，5.97(1H，d，J＝11.3Hz)，5.43(1H，d，J＝11.9Hz)，5.23(1H，s)，4.86(1H，d，J＝4.7Hz)，4.75(1H，d，J＝1.7Hz)，4.54(1H，d，J＝3.6Hz)，4.21-4.16(1H，m)，4.02(1H，s)，4.05-3.95(1H，m)，2.77(1H，d，J＝11.7Hz)，2.50-2.29(2H，m)，2.16(1H，dd，J＝13.5，5.2Hz)，2.00-1.94(2H，m)，1.82-1.78(1H，m)，1.71-1.25(17H，m)，0.90(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 149.40,139.76,139.25,135.81,122.93 (q, J=287.5Hz), 122.35,117.88,117.11,109.75,76.78 (septet, J=29.6Hz), 68.41,68.35,65.07,56.55,55.98,46.15,44.86,44.59,43.11,40.34,38.76,36.05,28.98,23.13,22.80,21.83,29.50,20.07,17.93,14.57

MS HRES value of calculation: C ₃₃H ₄₂D ₆F ₆O ₄[M+Na] ⁺651.3725

Measured value: [M+Na] ⁺651.3726

Embodiment 37

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (575mg, 1.007mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.61mL, 0.98mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (303mg, 0.476mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 5 hours, and added saturated ammonium chloride solution (1ml) then and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (100ml).(3 * 70ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 64 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (60cm ³, lucifuge) go up with ethyl acetate as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (251mg, 85%).

{[α]}_{D}^{29} = 44.3

(c＝0.42，EtOH)

UVλmax(EtOH)：244nm(ε36100)，252nm(ε42319)，262nm(ε28518)

¹H NMR(DMSO-D6)：7.99(1H，s)，6.14-6.06(1H，m)，6.07(1H，d，J＝12.4Hz)，5.78(1H，d，J＝11.3Hz)，5.43(1H，d，J＝12.2Hz)，4.48(1H，d，J＝4.0Hz)，4.38(1H，d，J＝4.1Hz)，4.02(1H，s)，3.90-3.84(1H，m)，3.84-3.76(1H，m)，2.73(1H，d，J＝13.6Hz)，2.54-2.41(2H，m)，2.26(1H，br d，J＝10.4Hz)，2.07-1.97(3H，m)，1.72-1.18(19H，m)，0.90(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 139.25,139.18,134.60,122.94 (q, J=286.8Hz), 120.82,117.13,116.33,76.77 (septet, J=28.0Hz), 68.41,65.54,65.26,56.53,55.95,46.00,44.59,42.22,40.34,38.78,36.96,36.07,28.17,22.99,22.80,21.89,21.40,17.94,14.67

MS HRES value of calculation: C ₃₂H ₄₂D ₆F ₆O ₄[M+Na] ⁺639.3725

Measured value: [M+Na] ⁺639.3717

Embodiment 38

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23Z-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (520mg, 1.105mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.69mL, 1.10mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R, 3Z) 6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (314mg, 0.493mmol) solution in oxolane (1.5mL).Stirred this reactant mixture 5 hours 30 minutes (in the end one hour rise to-50 ℃ with temperature) from-70.Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (100ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil.This oily residue is used for next reaction.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (10ml, 1M/ oxolane).This mixture of restir 22 hours.Dissolve this mixture and water and saline (30ml+20ml) by adding ethyl acetate (150ml) and extract 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and to use hexane: ethyl acetate 1: 1 is as mobile phase eluting purification.The flow point that will comprise product and impurity is at pillar (50cm ³, lucifuge) to go up and to use hexane: ethyl acetate-2: 1 and 1: 1 are as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (258mg, 83%).

{[α]}_{D}^{28} = + 25.0

(c＝0.44，EtOH)

UV λmax(EtOH)：210nm(ε15800)，245nm(ε15638)，269nm(ε15445)

¹H NMR(DMSO-D6)：7.99(1H，s)，6.36(1H，d，J＝11.3Hz)，6.10(1H，dt，J＝11.9，6.3Hz)，5.92(1H，d，J＝11.3Hz)，5.43(1H，d，J＝12.4Hz)，5.39(1H，s)，5.14(1H，ddd，J＝49.4，5.5，3.7Hz)，4.98(1H，d，J＝1.7Hz)，4.85(1H，d，J＝4.5Hz)，4.02(1H，s)，3.93-3.87(1H，m)，2.81(1H，d，J＝12.8Hz)，2.54-2.40(2H，m)，2.16-1.97(4H，m)，1.82-1.17(17H，m)，0.89(3H，s)，0.59(3H，s)

¹³C NMR (DMSO-D6): 143.13 (d, J=16.7Hz), 141.74,139.20,132.94,124.06,122.93 (q, J=286.0Hz), 117.26,117.12,115.18 (d, J=9.1Hz), 91.95 (d, J=166.9Hz), 76.78 (septet, J=28.8Hz), 68.41,64.54,65.50,56.51,55.92,46.24,44.81,44.58,40.68 (d, J=20.5Hz), 40.28,38.97,38.78,36.07,28.33,23.06,22.74,21.83,21.40,17.93,14.59

MS HRES value of calculation: C ₃₃H ₄₁D ₆F ₇O ₃[M+Na] ⁺653.3682

Measured value: [M+Na] ⁺653.3686

Embodiment 39

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol synthetic

(6R, 3E)-6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

Stirring rod is installed and has to one and pack lithium aluminium hydride reduction (13.00mL, 13.00mmol, 1M/ oxolane) in the 25mL round-bottomed flask of condenser of nitrogen purging into and this mixture is cooled to 0 ℃.Slowly add Feldalat NM (702mg, 13.00mmol), add (6R)-6-[(1R, 3aR then, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, 1,1-three fluoro-2-trifluoromethyl-11-3-alkynes-2,10-glycol (810mg, 1.665mmol) solution in oxolane (8ml).Stir 6.5 hours postcooling to 0 of these reactant mixtures ℃ at 80 ℃.Slowly add saturated ammonium chloride solution (5mL), add saturated ammonium chloride solution (60mL) and 2NHCl (20mL) then.(3 * 50ml) extract this mixture, dry (Na with ethyl acetate ₂SO ₄) and evaporation.

With the oily residue through chromatography at pillar (75cm ³) going up and to use hexane: ethyl acetate-2: 1 and 1: 1 are as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain water white oil (806mg, 98%).

¹H NMR(CDCl ₃)：6.28(1H，dt，J＝15.4，7.7Hz)，5.59(1H，d，J＝15.7Hz)，4.08(1H，br s)，2.13-2.00(3H，m)，1.83-1.79(2H，m)，1.63-1.24(18H，m)，1.08(3H，s)，0.97(3H，s)

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate (1.600g, 4.253mmol) and dichloromethane (15mL).Dropwise add (6R, 3E)-and 6-[(1R, 3aR, 4S, 7aR)-4-hydroxyl-7a-methyl-octahydro-indenes-1-yl]-6-

methyl isophthalic acid

1,11,11-three deuterium generation-10-three deuteriums are for methyl isophthalic acid, and 1,1-three fluoro-2-trifluoromethyl-11-3-alkene-2, the 10-glycol (782mg, the 1.581mmol) solution in dichloromethane (2mL), and at room temperature stirred this mixture 4 hours 30 minutes.

With this reactant mixture at silica gel (25cm ³) on the post with dichloromethane, dichloromethane: ethyl acetate is filtered at 4: 1.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (746mg, 96%).

(1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-5-hydroxyl-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-the 5-trifluoromethyl-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (746mg, 1.515mmol) and dichloromethane (10mL).Dropwise add 1-(TMS) imidazoles (1.90mL, 12.95mmol).At room temperature stirred this mixture 3 hours.(3 * 50ml) wash this mixture, dry (Na to add hexane (150ml) and water ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³) going up and use hexane: ethyl acetate-5: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain product, are water white oil (917mg, 95%).

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (460mg, 0.789mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.49mL, 0.78mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (302mg, 0.474mmol) solution in oxolane (1.5ml).Stir this reactant mixture 5.5h (in the end a hour from-70 rise to-50 ℃ with temperature).Add saturated ammonium chloride solution (1ml) and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).With ethyl acetate (3 * 50ml) extraction water parts, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point that will contain the chemical compound of product and the single deprotection of part merges and evaporation, obtains colorless oil.

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 18 hours.Dissolve this mixture and water (50mL) and saline (50ml) by adding ethyl acetate (150ml) and wash 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and carry out purification (oxolane is used for transfer of material to pillar) as mobile phase with ethyl acetate.The flow point that contains product comprises some impurity.The flow point merging and the evaporation that will comprise product obtain white solid.Solid phase is transferred to buchner funnel (10-15 μ m) with hexane, removes impurity with hexane (20mL) washing.Use ethanol (25mL) that product is shifted from funnel then, evaporating liquid obtains product, is white solid (215mg, 71%).

{[α]}_{D}^{27} = + 16.1

(c＝0.44，EtOH)

UVλmax(EtOH)：214nm(ε1377)，265nm(ε1675)

¹H NMR(DMSO-D6)：8.05(1H，s)，6.28(1H，dt，J＝15.3，7.7Hz)，6.18(1H，d，J＝11.1Hz)，5.97(1H，d，J＝11.3Hz)，5.62(1H，d，J＝15.3Hz)，5.22(1H，s)，4.87(1H，d，J＝4.7Hz)，4.75(1H，d，J＝2.1Hz)，4.55(1H，d，J＝3.6Hz)，4.21-4.16(1H，m)，4.04(1H，s)，4.05-3.95(1H，m)，2.79-2.76(1H，m)，2.35(1H，d，J＝13.9Hz)，2.16(1H，dd，J＝13.3，5.2Hz)，2.07(2H，d，J＝7.5Hz)，2.00-1.90(2H，m)，1.82-1.78(1H，m)，1.65-1.55(6H，m)，1.43-1.24(10H，m)，0.90(3H，s)，0.61(3H，s)

¹³C NMR (DMSO-D6): 149.37,139.67,136.44,135.84,122.60 (q, J=286.8Hz), 122.35,119.82,117.93,109.79,75.49 (septet, J=28.8Hz), 68.39,65.06,56.36,56.01,46.20,44.87,44.56,43.11,41.06,40.43,28.33,23.09,22.49,21.80,21.60,17.90,14.59

MS HRES value of calculation: C ₃₃H ₄₂D ₆F ₆O ₄[M+Na] ⁺651.3725

Measured value: [M+Na] ⁺651.3729

Embodiment 40

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro-19-fall-cholecalciferol synthetic

1,25-dihydroxy-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro-19-falls-cholecalciferol

(1R packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (584mg, 1.023mmol) and oxolane (8ml).With this reactant mixture be cooled to-70 ℃ and dropwise add n-BuLi (0.63mL, 1.01mmol).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (308mg, 0.484mmol) solution in oxolane (1.5ml).Stirred this reactant mixture 6 hours, and added saturated ammonium chloride solution (1ml) then and remove cooling bath.Pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will contain the chemical compound of product and the single deprotection of part obtain water white oil.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (15ml, 1M/ oxolane).This mixture of restir 96 hours.Dissolve this mixture and water (50mL) and saline (50ml) by adding ethyl acetate (150ml) and wash 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) to go up and to use hexane: oxolane-1: 1,1: 2 carry out purification (oxolane comprises some impurity) as mobile phase.The flow point merging and the evaporation that will comprise product obtain white solid.Solid phase is transferred to buchner funnel (10-15 μ m) and removes impurity with hexane (20mL) washing with hexane.Use ethanol (25mL) that product is shifted from funnel then, evaporating liquid obtains product, is white solid (274mg, 92%).

{[α]}_{D}^{27} = + 48.2

(c＝0.44，EtOH)

UVλmax(EtOH)：244nm(ε35585)，252nm(ε41634)，262nm(ε28023)

¹H NMR(DMSO-D6)：8.05(1H，s)，6.29(1H，dt，J＝15.6，7.7Hz)，6.07(1H，d，J＝11.3Hz)，5.78(1H，d，J＝11.3Hz)，5.62(1H，d，J＝15.6Hz)，4.48(1H，d，J＝4.1Hz)，4.38(1H，d，J＝3.8Hz)，4.04(1H，s)，3.90-3.84(1H，m)，3.83-3.76(1H，m)，2.73(1H，d，J＝13.2Hz)，2.43(1H，dd，J＝12.9，3.3Hz)，2.26(1H，d，J＝10.4Hz)，2.09-1.91(6H，m)，1.69-1.24(17H，m)，0.91(3H，s)，0.60(3H，s)

¹³C NMR (DMSO-D6): 139.10,136.46,134.64,122.59 (q, J=286.0Hz), 120.80,119.84,116.38,75.50 (septet, J=28.8Hz), 68.40,65.54,65.25,56.36,55.98,46.04,44.56,42.22,41.07,40.43,36.96,28.16,22.95,22.50,21.85,21.50,17.90,14.70

MS HRES value of calculation: C ₃₂H ₄₂D ₆F ₆O ₄[M+Na] ⁺639.3725

Measured value: [M+Na] ⁺639.3725

Embodiment 41

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol synthetic

1 α-fluoro-25-hydroxyl-20R-20-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-23E-alkene-26,27-hexafluoro cholecalciferol

(1S packs in a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (543mg, 1.154mmol) and oxolane (8ml).This reactant mixture is cooled to-70 ℃ also dropwise adds n-BuLi (0.72mL, 1.15mmol)).Stirred the gained dark red solution 20 minutes at-70 ℃, dropwise add (1R, 3aR, 7aR)-the 7a-methyl isophthalic acid-[(1R, 3E)-6,6,6-three fluoro-1-methyl isophthalic acids-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-5-trifluoromethyl-5-TMS oxygen base-oneself-the 3-thiazolinyl]-octahydro-indenes-4-ketone (279mg, 0.438mmol) solution in oxolane (1.5mL).Stirred this reactant mixture 8 hours (in the end one hour rise to-50 ℃ with temperature) from-70.Remove cooling bath and pour this mixture into ethyl acetate (50ml) and saturated ammonium chloride solution (50ml).(3 * 50ml) extract this water section, dry (Na with ethyl acetate ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate-10: 1 is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain grease.This oily residue is used for next reaction.In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into reaction substrate and tetrabutylammonium (8ml, 1M/ oxolane).This mixture of restir 25 hours.Adding ethyl acetate (150ml) is dissolved this mixture and water and saline (30ml+20ml) and is extracted 6 times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and to use hexane: ethyl acetate 2: 1,1: 1 is carried out purification as mobile phase.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.With this oil be dissolved in methyl acetate and the evaporation (4 times) obtain product, be white foam shape (216mg, 78%).

{[α]}_{D}^{28} = + 32.5

(c＝0.48，EtOH)

UVλmax(EtOH)：211nm(ε16931)，243nm(ε17696)，269nm(ε17736)

¹H NMR(DMSO-D6)：8.05(1H，s)，6.36(1H，d，J＝11.3Hz)，6.28(1H，dt，J＝15.6，7.6Hz)，5.92(1H，d，J＝11.3Hz)，5.62(1H，d，J＝15.3Hz)，5.39(1H，s)，5.14(1H，br d，J＝49.7Hz)，4.99(1H，d，J＝1.7Hz)，4.86(1H，d，J＝4.3Hz)，4.04(1H，s)，3.94-3.86(1H，m)，2.81(1H，d，J＝12.4Hz)，2.15-2.06(4H，m)，1.99-1.91(3H，m)，1.82-1.55(6H，m)，1.46-1.20(10H，m)，0.90(3H，s)，0.59(3H，s)

¹³C NMR (DMSO-D6): 143.29 (d, J=17.4Hz), 141.83,136.58,133.13 (d, J=1.5Hz), 124.20,122.76 (q, J=287.5Hz), 119.99,117.46,115.39 (d, J=9.9Hz), 92.09 (d, J=166.8Hz), 75.57 (septets, J=28.8Hz), 68.48,64.60,64.56,56.40,56.02,46.31,44.86,44.58,41.11,40.71 (d, J=20.4Hz), 40.43,39.36,28.34,23.02,22.44,21.79,21.50,17.90,14.60

MS HRES value of calculation: C ₃₃H ₄₁D ₆F ₇O ₃[M+Na] ⁺653.3682

Measured value: [M+Na] ⁺653.3684

Embodiment 42

1,25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol synthetic

(1R, 3aR, 4S, 7aR)-2-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl } ethyltoluene-4-sulphonic acid ester

(the 1R of 5.98g (16.958mmol) packs in a 100mL round-bottomed flask that stirring rod and nitrogen purging be installed, 3aR, 4S, 7aR)-2-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-4-dimethylaminopyridine of ethanol, 50mL dichloromethane, 6mL triethylamine and 230mg (1.883mmol).The toluene sulfochloride of disposable adding 4.83g (25.334mmol).At room temperature stirred this mixture 2 hours.This suspension is poured in the mixture of 40g ice, 100mL saturated sodium bicarbonate solution and 100mL hexane.Water layer extracts three times with the 50mL dichloromethane again.With the extract that the water washing of 100mL salt merges, use Na ₂SO ₄Dry also evaporation.The flash chromatography post hexane of residue through lacking: ethyl acetate (20: 1) obtains the 9.0g crude product as mobile phase eluting purification, is water white oil.Product need not be further purified and be directly used in next reaction.

(1R, 3aR, 4S, 7aR)-2-(2-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-ethyl)-dimethyl malenate

At one mechanical splash bar is installed, has the 160mL toluene of packing in the three neck round-bottomed flasks of 500mL of funnel of nitrogen purging and condenser in addition.Disposable adding 5.20g (130mmol) sodium hydride (60% dispersion in mineral oil).In the suspension of this stirring, dropwise add the solution of 19.36g (146.5mmol) dimethyl malenate in 50mL toluene.This jelly was heated 10 minutes in 120 ℃ of oil baths, thick (the 1R that dropwise adds 9.0g (about 16.958mmol) then, 3aR, 4S, 7aR)-2-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl } ethyltoluene-solution of 4-sulphonic acid ester in 100mL toluene.Stirring reaction is 6 hours under this temperature.This flask is placed ice bath and adds the precipitation that 100mL cold water dissolves large volume.Come this mixture of balance with the 100mL hexane.The gained water extracts three times with 50mL toluene again.With the extract that 100mL water and the water washing of 50mL salt merge, use Na then ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (500cm ³) go up and use hexane: ethyl acetate (20: 1; 15: 1) as the mobile phase eluting and collect the flow point of about 50ml.The flow point that will comprise product merges and evaporation.It is merged individually, evaporates for the flow point of mixture, and once more at chromatographic column (300cm ³) going up and use hexane: ethyl acetate (20: 1) is as the flow point of mobile phase eluting and the about 25mL of collection.The flow point that will comprise product merges, and evaporation obtains 6.148g (two step gross production rates are 78%) product, is water white oil.

(1R, 3aR, 4S, 7aR)-4-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-methyl butyrate

To (a 1R who stirring rod is installed and has 6.11g (13.091mmol) that pack in the 100mL round-bottomed flask of condenser of nitrogen purging, 3aR, 4S, 7aR)-2-(2-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-ethyl)-mixture and 1.11g (26.185mmol) lithium chloride of dimethyl malenate, 25mL dimethyl sulfoxide and water (100: 1).Stir this mixture and in nitrogen, descend heating 3 hours in 160 ℃.Cool off this solution then and, use 50mL hexane extraction water layer three times with 100mL water and the distribution of 200mL hexane.The organic layer that merges with 50mL water and the water washing of 50mL salt five times is used Na then ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (500cm ³) going up and use hexane: ethyl acetate (50: 1) is as the flow point of mobile phase eluting and the about 50ml of collection.The flow point merging and the evaporation that will comprise product obtain water white oil.It is merged individually, evaporates for the flow point of mixture, and once more at chromatographic column (160cm ³) go up and use hexane: ethyl acetate (50: 1) eluting purification.Obtain 4.19g (78%) product.

¹H NMR(CDCl ₃)：3.98(1H，br s)，3.66(3H，s)，2.29-2.23(2H，m)，2.10-1.75(5H，m)，1.68-1.22(10H，m)，0.94(3H，s)，0.88(9H，s)，0.71-0.65(1H，m)，0.61-0.50(1H，m)，0.21-0.14(2H，m)，0.00(3H，s)，-0.02(3H，s)，-0.05-0.12(1H，m)。

(1R, 3aR, 4S, 7aR)-5-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-1,1,1-three deuterium generation-2-three deuterium acute pyogenic infection of nails base-pentane-2-alcohol

At one stirring rod is installed, has (the 1R of 3.012g (7.370mmol) that pack in the 250mL round-bottomed flask of Clarkson joint of rubber septum, 3aR, 4S, 7aR)-4-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-methyl butyrate and 75mL absolute ether.This solution of cooling also dropwise adds 1M methyl-d of 20mL (20mmol) in ice-water bath ₃The solution of-magnesium iodide in ether.At room temperature stirred this mixture after adding 1.5 hours, cooling once more in ice bath then.Dropwise add the 25mL saturated ammonium chloride solution.Dissolve the gained precipitation by adding 100mL water.With 50mL ether aqueous layer extracted three times again.The ether layer Na that merges ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (350cm ³) going up and use hexane: ethyl acetate (9: 1) is as the flow point of mobile phase eluting and the about 50mL of collection.The flow point merging and the evaporation that will comprise product obtain water white oil.It is merged individually, evaporates for the flow point of mixture, and once more at chromatographic column (100cm ³) go up and use hexane: ethyl acetate (9: 1) eluting purification.Obtain 2.95g (96%) product.

¹H NMR(CDCl ₃)：3.99(1H，br s)，2.05-1.76(4H，m)，1.68-1.17(14H，m)，0.95(3H，s)，0.88(9H，s)，0.70-0.52(2H，m)，0.22-0.12(2H，m)，0.01(3H，s)，-0.01(3H，s)，-0.05--0.11(1H，m)。

(1R, 3aR, 4S, 7aR)-1-[1-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-cyclopropyl]-7a-methyl-octahydro-indenes-4-alcohol

(the 1R of 2.940g (7.088mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 4S, 7aR)-5-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-octahydro-indenes-1-yl]-cyclopropyl }-1,1, the solution of 1.0M tetrabutylammonium in oxolane of 1-three deuterium generation-2-three deuterium acute pyogenic infection of nails base-pentanes-pure and mild 25mL of 2-(25.0mmol).Stir this reactant mixture 22 hours at 70 ℃, add the tetrabutylammonium of new a collection of 10mL (10.0mmol).This reactant of 70 ℃ of restir 26 hours.Dissolve this mixture by adding 150mL ethyl acetate and also use 40mL water and the water washing of 20mL salt six times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (250cm ³) going up and use hexane: ethyl acetate (3: 1) is as mobile phase eluting purification.The flow point merging and the evaporation that will comprise product obtain 2.00g (94%) product.

(1R, 3aR, 7aR)-1-[1-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-cyclopropyl]-7a-methyl-octahydro-indenes-4-ketone

In a 250mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into pyridinium dichromate, 7.28g kieselguhr and the 75mL dichloromethane of 7.42g (19.723mmol).(1R, 3aR, the 4S that dropwise add 1.96g (6.522mmol), 7aR)-1-[1-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-cyclopropyl]-the 7a-methyl-octahydro-indenes-solution of 4-alcohol in the 5mL dichloromethane, and at room temperature stirred this mixture 6 hours.With this reactant mixture at 100cm ³Use dichloromethane and dichloromethane on the silica gel: ethyl acetate (4: 1,3: 1,2: 1) filter as mobile phase.To comprise the flow point merging of product and the ketone that evaporation obtains 1.92g (98%).

¹H NMR(CDCl ₃)：2.50(1H，dd，J＝11.4，7.0Hz)，2.29-2.12(4H，m)，2.05-1.86(3H，m)，1.75-1.17(9H，m)，1.08-0.98(1H，m)，0.73-0.60(2H，m)，0.69(3H，s)，0.26-0.19(2H，m)，0.06--0.01(1H，m)。

(1R, 3aR, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-octahydro-indenes-4-ketone

(the 1R of 1.91g (6.399mmol) packs in a 100mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, 3aR, 7aR)-1-[1-(4-hydroxyl-5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails base-amyl groups)-cyclopropyl]-7a-methyl-octahydro-indenes-4-ketone and 60mL dichloromethane.1-(TMS) imidazoles that dropwise adds 3.8mL (25.90mmol).At room temperature stirred this mixture 1 hour 45 minutes.Add 25mL water and stirred this mixture 10 minutes.Dissolve the gained mixture by adding 200mL water.With 50mL ethyl acetate extraction water layer five times.With the organic layer that the water washing of 50mL salt merges, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (200cm ³) go up and use hexane: dichloromethane (2: 1,1: 1) and dichloromethane are as the mobile phase eluting.To comprise the flow point merging of product and the product that evaporation obtains 2.10g (89%), be water white oil.

1 α, 25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol

(the 1R of 2.155g (3.776mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 3R)-1,3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction and 15mL anhydrous tetrahydro furan.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in hexane that also dropwise add 2.3mL (3.68mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 700mg (1.888mmol), 3aR, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-octahydro-indenes-solution of 4-ketone in the 2mL anhydrous tetrahydro furan.Stirred this reactant mixture 4 hours, and removed cooling bath then and pour this mixture into 50mL ethyl acetate and 50mL saline.With 75mL ethyl acetate extraction water section three times.Merge whole organic layers, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (100cm ³, lucifuge) go up and use hexane: ethyl acetate (20: 1) is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1.0M tetrabutylammonium in oxolane of 20mL.At room temperature stirred this reactant mixture 24 hours.Dissolve this mixture by adding the 150mL ethyl acetate.With 50mL water and 50mL salt water washing organic layer five times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up with ethyl acetate as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This oil is dissolved in methyl acetate and evaporates the white foam shape product that (4 times) obtain 525mg (66%).

[α] ³⁰ _D＝+47.8c 0.46，CHCl ₃

UV λmax(EtOH)：243nm(ε32133)，251nm(ε37757)，261nm(ε25993)

¹H NMR(CDCl ₃)：6.30(1H，d，J＝11.3Hz)，5.82(1H，d，J＝11.3)，4.15-4.08(1H，m)，4.07-4.00(1H，m)，2.82-2.78(1H，m)，2.73(1H，dd，J＝13.1，3.7Hz)，2.48(1H，dd，J＝13.3，3.3Hz)，2.24-1.24(21H，m)，1.19(1H，s)，1.00-0.91(1，m)，0.68-0.61(2H，m)，0.59(3H，s)，0.23-0.17(2H，m)，0.05--0.05(1H，m)

MS HRES value of calculation: C ₂₇H ₃₈D ₆FO ₃[M+Na] ⁺445.3559

Measured value: [M+Na] ⁺445.3561

Embodiment 43

Acetic acid 1 α-acetoxyl group-25-hydroxyl-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol base ester synthetic

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1 α of 245mg (0.579mmol), 25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol and 6mL pyridine.Stir this mixture down and dropwise add 1mL (10.6mmol) acetic anhydride at 0-5 ℃.Stir this reactant mixture 17 hours at 0-5 ℃, dropwise add the acetic anhydride of new a collection of 0.75mL (7.9mmol).This reactant mixture of restir 24 hours.Dissolve this mixture by adding 10mL water, stirred 15 minutes and poured in the 100mL ethyl acetate.Extract this mixture five times with 50mL water and 50mL saline, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (2: 1) is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product is dissolved in methyl acetate and evaporates the white foam shape product that (4 times) obtain 259mg (88%).

[α] ³⁰ _D＝+8.2c 0.45，CHCl ₃

UVλmax(EtOH)：243nm(ε34931)，251nm(ε40870)，260nm(ε27807)

¹H NMR(CDCl ₃)：6.25(1H，d，J＝11.1Hz)，5.72(1H，d，J＝11.5Hz)，5.12-5.06(2H，m)，2.80-2.76(1H，m)，2.60-2.44(3H，m)，2.27(1H，dd，J＝13.5，7.7Hz)，2.14-1.87(6H，m)，2.03(3H，s)，2.00(3H，s)，1.70-1.25(11H，m)，1.18(1H，s)，1.00-0.91(1H，m)，0.68-0.60(2H，m)，0.57(3H，s)，0.23-0.16(2H，m)，0.00--0.06(1H，m)

MS HRES value of calculation: C ₃₁H ₄₂D ₆FO ₅[M+Na] ⁺529.3770

Measured value: [M+Na] ⁺529.3782

Embodiment 44

1 α, 25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols

(the 1S of 2.201g (3.774mmol) packs in a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed; 5R)-1,5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction and 15mL anhydrous tetrahydro furan.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in hexane that also dropwise add 2.3mL (3.68mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 700mg (1.888mmol), 3aR, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-octahydro-indenes-solution of 4-ketone in the 2mL anhydrous tetrahydro furan.Stirred this reactant mixture 4 hours, and removed cooling bath then and also this mixture is poured in 60mL ethyl acetate and the 50mL saline.With this water section of 75mL ethyl acetate extraction, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (100cm ³, lucifuge) go up and use hexane: ethyl acetate (20: 1) is carried out purification as mobile phase.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1.0M tetrabutylammonium in oxolane of 20mL.At room temperature stirred this reactant mixture 24 hours.Dissolve this mixture by adding 150mL ethyl acetate and also use 50mL water and the water washing of 50mL salt five times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up with ethyl acetate as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.Part comprises the flow point of impurity at pillar (50cm ³, lucifuge) to go up and use ethyl acetate: hexane (2: 1) is as the mobile phase purification.This product is dissolved in methyl acetate and evaporates the white foam shape product that (4 times) obtain 749mg (91%).

[α] ³⁰ _D＝+3.3c 0.46，CHCl ₃

UVλmax(EtOH)：213nm(ε12528)，264nm(ε14832)

¹H NMR(CDCl ₃)：6.37(1H，d，J＝11.5Hz)，5.99(1H，d，J＝11.1)，5.32(1H，s)，4.99(1H，s)，4.44-4.42(1H，m)，4.23(1H，br s)，2.84-2.80(1H，m)，2.59(1H，dd，J＝13.5，3.5Hz)，2.31(1H，dd，J＝13.4，6.4Hz)，2.13-2.09(1H，m)，2.06-1.88(5H，m)，1.73-1.26(13H，m)，1.18(1H，br s)，0.99-0.90(1H，m)，0.68-0.61(2H，m)，0.59(3H，s)，0.21-0.16(2H，m)，0.00--0.06(1H，m)

MS HRES value of calculation: C ₂₈H ₃₈D ₆FO ₃[M+Na] ⁺457.3559

Measured value: [M+Na] ⁺457.3563

Embodiment 45

Acetic acid 1 α-acetoxyl group-25-hydroxyl-20-cyclopropyl-26,27-six deuterium generation-cholecalciferol base esters

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1 α of 345mg (0.794mmol), 25-dihydroxy-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols and 7mL pyridine.Stir this mixture and dropwise add 1.5mL (15.9mmol) acetic anhydride at 0-5 ℃.Stir this reactant mixture 17 hours at 0-5 ℃, add the acetic anhydride of new a collection of 0.5mL (5.3mmol).1mL (10.6mmol) acetic anhydride that adds next group after 25 hours.This reactant mixture of restir 16 hours.Dissolve this mixture by adding 15mL water, stirred 15 minutes and poured in the 120mL ethyl acetate.Extract this mixture five times with 50mL water and 50mL saline, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up and use hexane: ethyl acetate (2: 1) is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product is dissolved in methyl acetate and evaporates the white foam that (4 times) obtain 364mg (88%).

[α] ³⁰ _D＝-20.2c 0.46，CHCl ₃

UV λmax(EtOH)：207nm(ε14863)，250nm(ε15225)，265nm(ε15985)

¹H NMR(CDCl ₃)：6.34(1H，d，J＝11.3Hz)，5.89(1H，d，J＝11.5Hz)，5.47(1H，dd，J＝6.2，4.0Hz)，5.30(1H，s)，5.21-5.15(1H，m)，5.03(1H，d，J＝1.7Hz)，2.82-2.78(1H，m)，2.64(1H，dd，J＝13.2，4.3Hz)，2.38-2.33(1H，m)，2.13-1.92(6H，m)，2.05(3H，s)，2.03(3H，s)，1.72-1.28(11H，m)，1.19(1H，s)，0.98-0.88(1H，m)，0.68-0.59(2H，m)，0.56(3H，s)，0.22-0.16(2H，m)，0.01--0.06(1H，m)

MS HRES value of calculation: C ₃₂H ₄₂D ₆FO ₅[M+Na] ⁺541.3770

Measured value: [M+Na] ⁺541.3764

Embodiment 46

1 α-fluoro-25-hydroxyl-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols

In a 50mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1.907g (4.052mmol) (1S, 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction and 15mL anhydrous tetrahydro furan.This reactant mixture is cooled to-78 ℃ of 1.6M n-BuLi solution in hexane that also dropwise add 2.5mL (4.00mmol).Stirred the gained dark red solution 20 minutes at-78 ℃, (the 1R that dropwise adds 650mg (1.754mmol), 3aR, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-octahydro-indenes-solution of 4-ketone in the 2mL anhydrous tetrahydro furan.Stirred this reactant mixture 3.5 hours, and removed cooling bath then and also this mixture is poured in 60mL ethyl acetate and the 50mL saline.With this water section of 60mL ethyl acetate extraction four times, dry (Na ₂SO ₄) and evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up and use hexane: ethyl acetate-20: 1 is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain water white oil, and it uses the solution-treated of 1.0M tetrabutylammonium in oxolane of 20mL.At room temperature stirred this reactant mixture 7.5 hours.Dissolve this mixture by adding 150mL ethyl acetate and also use 50mL water and the water washing of 50mL salt five times, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (75cm ³, lucifuge) go up and use hexane: ethyl acetate (1: 1) is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.Part comprises the flow point of impurity at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (2: 1) is as mobile phase eluting purification.This product is dissolved in methyl acetate and evaporates the white foam that (4 times) obtain 629mg (82%).

[α] ³⁰ _D＝+22.1c 0.43，CHCl ₃

UVλmax(EtOH)：209nm(ε14376)，243nm(ε13949)，269nm(ε14083)

¹H NMR(CDCl ₃)：6.39(1H，d，J＝11.1Hz)，6.00(1H，d，J＝11.1Hz)，5.38(1H，s)，5.13(1H，ddd，J＝49.5，6.9，3.7Hz)，5.09(1H，s)，4.22(1H，br s)，2.84-2.80(1H，m)，2.62(1H，dd，J＝13.3，3.7Hz)，2.30(1H，dd，J＝13.3，7.5Hz)，2.23-1.92(6H，m)，1.74-1.26(12H，m)，1.18(1H，s)，0.98-0.91(1H，m)，0.68-0.61(2H，m)，0.59(3H，s)，0.21-0.16(2H，m)，0.00--0.06(1H，m)

MS HRES value of calculation: C ₂₈H ₃₇D ₆FO ₂[M+Na] ⁺459.3516

Measured value: [M+Na] ⁺459.3521

Embodiment 47

Acetic acid 1 α-fluoro-25-hydroxyl-20-cyclopropyl-26,27-six deuterium generation-cholecalciferol base esters

In a 25mL round-bottomed flask of Clarkson joint that stirring rod and band rubber septum be installed, pack into 1 α-fluoro-25-hydroxyl-20-cyclopropyl-26 of 300mg (0.687mmol), 27-six deuterium generation-cholecalciferols and 6mL pyridine.Stir this mixture and dropwise add 1mL (10.6mmol) acetic anhydride at 0-5 ℃.Stirred this reactant mixture 16 hours and added new a collection of 0.5mL (5.3mmol) acetic anhydride at 0-5 ℃.This reactant mixture of restir 3 hours.Dissolve this mixture by adding 15mL water, stirred 15 minutes and poured in the 120mL ethyl acetate.Extract this mixture five times with 50mL water and 50mL saline, use Na ₂SO ₄Dry also evaporation.With the oily residue through chromatography at pillar (50cm ³, lucifuge) go up and use hexane: ethyl acetate (3: 1) is as the mobile phase eluting.The flow point merging and the evaporation that will comprise product obtain product, are water white oil.This product is dissolved in methyl acetate and evaporates the white foam that (4 times) obtain 292mg (89%).

[α] ³⁰ _D＝-15.9c 0.46，CHCl ₃

UVλmax(EtOH)：210nm(ε11176)，245nm(ε10496)，264nm(ε10387)

¹H NMR(CDCl ₃)：6.36(1H，d，J＝11.3Hz)，6.00(1H，d，J＝11.3Hz)，5.40(1H，s)，5.23-5.16(1H，m)，5.10(1H，dm，J＝49.7Hz)，5.10(1H，s)，2.82-2.79(1H，m)，2.64(1H，dd，J＝13.7，3.7Hz)，2.41-2.36(1H，m)，2.23-1.93(6H，m)，2.04(3H，s)，1.73-1.26(12H，m)，0.99-0.92(1H，m)，0.68-0.61(2H，m)，0.60(3H，s)，0.22-0.17(2H，m)，0.00--0.06(1H，m)

MS HRES value of calculation: C ₃₀H ₃₉D ₆FO ₃[M+Na] ⁺501.3621

Measured value: [M+Na] ⁺501.3619

Embodiment 48

1,25-dihydroxy-16-alkene-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol synthetic

(3aR, 4S, 7aR)-and 1-E/Z-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl])-cyclopropyl }-2-methoxyl group-vinyl

At room temperature to the pyridinium chlorochromate (10.3g that stirred, 47.7mmol) in the suspension of dichloromethane (100mL), dropwise add (3aR, 4S, 7aR)-{ 1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl }-methanol (6.5g, 19.31mmol) solution in dichloromethane (10.0mL).Stirred this reactant mixture 1.0 hours and filter through kieselguhr/silicagel column (20g+50g), it uses the solution washing of 10%AcOEt in hexane then, obtain thick (3aR, 4S, 7aR)-1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl formaldehyde (5.6g).(7.5g 21.88mmol) dropwise adds two (TMS) Sodamide. (22mL, 22mmol, the 1.0M solution in THF) in the suspension of oxolane (150mL) to (methoxy) triphenyl phosphonium chloride that stirred at 0 ℃.After 30 minutes, under 0 ℃, dropwise add (3aR, 4S, 7aR)-1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl formaldehyde (5.6g, 16.74mmol) solution in oxolane (20mL).Stirred this reactant mixture 1 hour at 0 ℃, add entry (150mL) then, (2 * 150mL) extract this reactant and use Na with hexane ₂SO ₄Dry.Residue behind evaporating solvent (12.5g) obtains title compound (5.41g, 14.92mmol, 77%) through FC (200g, hexane, the 5%AcOEt solution in hexane) purification.

(3aR, 4S, 7aR)-and 1-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl])-cyclopropyl }-acetenyl

At room temperature to the (3aR that stirred, 4S, 7aR)-1-E/Z-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl])-cyclopropyl }-(5.41g 14.92mmol) adds tart acid (25mL) and with this reactant mixture reflux 72 hours to 2-methoxyl group-vinyl in the solution of dichloromethane (50mL).Add NaHCO ₃Also (2 * 200mL) extract this reactant mixture to aqueous solution (350mL), and (200mL) washs and use Na with saline with dichloromethane ₂SO ₄Dry, residue behind the evaporating solvent (1.2g) obtains (3aR through FC (150g, hexane, the 2%AcOEt solution in hexane) purification, 4S, 7aR)-{ 1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl }-acetaldehyde (3.65g, 10.47mmol).At room temperature to the (3aR that stirred, 4S, 7aR)-{ 1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl }-(3.65g 10.47mmol) adds (1-diazo-2-oxo-propyl group)-phosphonic acids dimethyl esters (3.0g, 15.61mmol) solution in methanol (5mL) to acetaldehyde in the solution of methanol (15mL).The gained mixture cooled off in ice bath and add potassium carbonate (3.07g, 22.21mmol, powder).This reactant mixture was stirred in ice bath 30 minutes, at room temperature stirred then 45 minutes.Also (2 * 150mL) extract this mixture with hexane to add entry (100mL).Wash the extract that merges and use Na with saline (100mL) ₂SO ₄Dry.Residue behind the evaporating solvent (3.9g) obtains title compound (2.6g, 7.54mmol, 72%) through FC (100g, hexane, the 2%AcOEt solution in hexane) purification.

[α] ²⁸ _D＝+29.8c 0.8，CHCl ₃

¹H NMR(CDCl ₃)：5.45(1H，br.s)，4.04(1H，br.s)，2.40(2H，m)，2.24(1H，m)，1.96-1.38(9H，m)，1.17(3H，s)，0.88(9H，s)，0.74-0.54(4H，m)，0.01(6H，s)；

¹³C NMR(CDCl ₃)：156.44(0)，125.39(1)，82.65(1)，69.39(0)，69.23(1)，55.92(1)，47.60(0)，36.42(2)，34.65(2)，30.76(2)，26.04(2)，20.34(3)，19.35(0)，18.30(2)，11.516(2)，10.97(2)，-4.55(3)，-4.87(3)；

MS HREI value of calculation C ₂₂H ₃₆OSi M+344.2535

Measured value M+344.2539

(3aR, 4S, 7aR)-and 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-penta-2-alkynyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol

At-78 ℃ to the (3aR that stirred, 4S, 7aR)-and 1-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl])-cyclopropyl }-(1.6g 4.64mmol) adds n-BuLi (4.35mL to acetenyl in the solution of oxolane (22mL), 6.96mmol, the solution of 1.6M in hexane).After 1 hour, add acetone-d-78 ℃ of stirrings ₆(1.0mL, 13.6mmol (D, 99,96) also continues to stir 2.5 hours.Add NH ₄Cl aqueous solution (15mL) also at room temperature stirred this mixture 15 minutes, used AcOEt (2 * 50mL) extractions then.Wash the extract that merges and use Na with saline (50mL) ₂SO ₄Dry.Residue behind the evaporating solvent (2.4g) obtains (3aR through FC (50g, the 10%AcOEt solution in hexane) purification, 4S, 7aR)-5-{1-[4-(tert-butyl group-dimethyl-silanyloxy base)-7a-methyl-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-1-yl]-cyclopropyl }-1,1,1-three deuterium generation-2-three deuterium acute pyogenic infection of nails bases-penta-3-alkynes-2-alcohol (1.81g, 4.43mmol), it is handled with tetrabutylammonium (12mL, 12mmol, the 1.0M solution in THF) and stirred 48 hours at 65-75 ℃.With AcOEt (25mL) dilute this mixture and water (5 * 25mL), saline (25mL) washing.The water layer that merges is with AcOEt (25mL) extraction and with the organic extract Na that merges ₂SO ₄Dry.Residue behind the evaporating solvent (2.5g) obtains title compound (1.21g, 4.11mmol, 89%) through FC (100g, the 20%AcOEt solution in hexane) purification.

[α] ³⁰ _D＝+2.0c 0.35，CHCl ₃

¹H NMR(CDCl ₃)：5.47(1H，m)，4.15(1H，m)，2.40(2H，s)，2.28(1H，ddd，J＝13.4，11.9，1.5Hz)，1.98-1.36(10H，m)，1.19(3H，s)，0.70-0.52(4H，m)；

¹³C NMR(CDCl ₃)：156.32(0)，125.22(1)，86.36(0)，80.33(0)，69.31(1)，69.14(0)，55.20(1)，47.01(0)，35.87(2)，33.70(2)，29.99(2)，27.34(2)，19.39(2)，19.29(0)，17.83(3)，11.05(2)，10.50(2)；

MS HREI value of calculation C ₁₉H ₂₂O ₂D ₆M+294.2466

Measured value M+294.2474

(3aR, 4S, 7aR)-and 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-penta-2Z-thiazolinyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol

With (3aR, 4S, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-penta-2-alkynyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (1.02g, 3.46mmol), (222mg, 5%Pd is at CaCO for ethyl acetate (14mL), hexane (31mL), dehydrated alcohol (1.25mL), quinoline (66 μ L) and Lindlar catalyst ₃On) mixture hydrogenation at room temperature 2 hours.This reactant mixture is washed this diatomite layer through the diatomite layer filtration and with AcOEt.Filtrate and cleaning mixture are merged, with HCl, the NaHCO of 1M ₃With the salt water washing.Use Na ₂SO ₄Drying, evaporating solvent and with residue (1.2g) through FC (75g, the 20%AcOEt solution in hexane) purification, obtain title compound (890mg, 3.0mmol, 87%).

[α] ²⁸ _D＝+1.7c 0.48，CHCl ₃

¹H NMR(CDCl ₃)：5.45(1H，dt，J＝11.9，1.8Hz)，5.42(1H，m，)，5.36(1H，dt，J＝12.1，6.3Hz)，4.14(1H，m)，2.43(1H，m)，2.27(1H，ddd，J＝13.6，12.2，1.7Hz)，2.00-1.24(11H，m)，1.18(3H，s)，0.70-0.36(4H，m)；

¹³C NMR(CDCl ₃)：156.67(0)，136.58(1)，128.65(1)，125.21(1)，71.48(0)，69.37(1)，55.28(1)，47.07(0)，35.89(2)，35.57(2)，33.68(2)，30.04(2)，21.14(0)，19.37(3)，17.84(2)，11.85(2)，11.06(2)；

MS HRES value of calculation C ₁₉H ₂₄O ₂D ₆M+H 296.2622

Measured value M+H 296.2619

(3aR, 4S, 7aR)-and 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-amyl groups)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol

Use the Paar device, at room temperature following to (3aR, 4S in 50psi pressure, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-penta-2Z-thiazolinyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (860mg, 2.9mmol), 1,4-two (diphenylphosphino)

butane

1,5 cyclo-octadiene rhodium tetrafluoroborates (200mg, 0.28mmol), the mixture hydrogenation of dichloromethane (35mL) and a hydrargyrum 2 hours.This reactant mixture filters through diatomite layer, washs with ethyl acetate then.The filtrate and the cleaning mixture that merge are evaporated to dried (950mg),, obtain title compound (600mg, 2.01mmol, 69%) through FC (100g, the 20%AcOEt solution in hexane) purification three times.

[α] ³⁰ _D＝-5.3c 0.45，CHCl ₃

¹H NMR(CDCl ₃)：5.37(1H，m，)，4.14(1H，m)，2.32-1.20(17H，m)，1.18(3H，s)，0.64-0.26(4H，m)；

¹³C NMR(CDCl ₃)：156.84(0)，124.87(1)，70.79(0)，69.39(1)，55.42(1)，47.19(0)，43.75(2)，38.31(2)，35.86(2)，33.69(2)，29.97(2)，22.35(2)，21.14(0)，19.46(3)，17.88(2)，12.19(2)，11.28(2)；

MS HREI value of calculation C ₁₉H ₂₆O ₂D ₆M+H 298.2779

Measured value M+H 298.2787

(3aR, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone

At room temperature to the (3aR that stirred, 4S, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-pentenyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-alcohol (450mg, 1.51mmol) and kieselguhr (2.0g) in the suspension of dichloromethane (10mL), add pyridinium dichromate (1.13g, 3.0mmol).The gained mixture was stirred 3.5 hours and filter, use the solution washing layer of silica gel of 25%AcOEt in hexane then through silica gel (10g).With filtrate and the cleaning mixture evaporation that merges, obtain thick (3aR, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-pentenyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (425mg, 1.44mmol, 95%).At room temperature to the (3aR that stirred, 7aR)-the 7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-hydroxyl-4-three deuterium acute pyogenic infection of nails base-pentenyls)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (425mg, 1.44mmol) in the solution of dichloromethane (10mL), add TMS-imidazoles (0.44mL, 3.0mmol).Stirred the gained mixture 1.0 hours and, used this layer of silica gel of the solution washing of 10%AcOEt in hexane through silica gel (15g) filtration.The filtrate and the cleaning mixture evaporation that merge are obtained title compound (450mg, 1.22mmol, 85%).

[α] ³⁰ _D＝-14.2c 0.43，CHCl ₃

¹H NMR (CDCl ₃): 5.33 (1H, dd, J=3.2,1.5Hz), 2.81 (1H, dd, J=10.7,6.4Hz), 2.44 (1H, ddd, J=15.8,10.7,1.6Hz), 2.30-1.12 (13H, m) overlapping 2.03 (ddd, J=15.9,6.4,3.2Hz), 0.92 (3H, s), 0.66-0.28 (4H, m), 0.08 (9H, s);

¹³C NMR(CDCl ₃)：210.74(0)，155.41(0)，124.81(1)，73.71(0)，64.37(1)，53.92(0)，44.67(2)，40.46(2)，38.21(2)，34.80(2)，26.86(2)，24.06(2)，22.28(2)，21.28(0)，18.40(3)，12.59(2)，10.69(2)，2.62(3)；

MS HRES value of calculation C ₂₂H ₃₂O ₂SiD ₆M+368.0318

Measured value M+368.3029

1 α, 25-dihydroxy-16-alkene-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol

At-78 ℃ to the (1R that stirred; 3R)-1; 3-two-((tert-butyl group dimethyl) silanyloxy base)-5-[2-(diphenylphosphine acyl group) second subunit]-cyclohexane extraction (536mg, 0.92mmol) in the solution of oxolane (7mL), add n-BuLi (0.58mL, 0.93mmol).Stirred the gained mixture 15 minutes, dropwise add (3aR, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (170mg, 0.46mmol) solution in oxolane (2mL).Stirred this reactant mixture 3.5 hours at-72 ℃, with hexane (35mL) dilution, (30mL) washs and uses Na with saline ₂SO ₄Dry.Residue behind the evaporating solvent (725mg) is through FC (15g, the solution of 5%AcOEt in hexane) purification, obtain 1 α, 3 β-two (tert-butyl group-dimethyl-silanyloxy base)-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26,27-six deuterium generation-19-fall-and cholecalciferol (293mg, 041mmol).

At room temperature to 1 α, 3 β-two (tert-butyl group-dimethyl-silanyloxy base)-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26,27-six deuterium generation-19-fall-cholecalciferol (293mg, 0.41mmol) the middle tetrabutylammonium (4mL that adds, 4mmol, the 1M solution in THF).Stirred this mixture 40 hours, with AcOEt (25mL) dilution, water (5 * 20mL), saline (20mL) washs and uses Na ₂SO ₄Dry.Residue behind the evaporating solvent (280mg) obtains title compound (163mg, 0.39mmol, 84%) through FC (15g, 50%AcOEt solution and the AcOEt in hexane) purification.

[α] ²⁹ _D＝+65.8c 0.40，EtOH

UV λmax(EtOH)：243nm(ε32702 251nm(ε39060)，261nm(ε26595)；

¹H NMR(CDCl ₃)：6.30(1H，d，J＝11.3Hz)，5.93(1H，d，J＝11.3Hz)，5.36(1H，m)，4.13(1H，m)，4.05(1H，m)，2.76(2H，m)，2.52-1.10(22H，m)，0.79(3H，s)，0.66-0.24(4H，m)；

¹³C NMR(CDCl ₃)：157.05(0)，142.25(0)，131.15(0)，124.66(1)，123.70(1)，115.44(1)，70.82(0)，67.42(1)，67.22(1)，59.51(1)，50.17(0)，44.66(2)，43.79(2)，42.22(2)，38.18(2)，37.25(2)，35.64(2)，29.19(2)，28.56(2)，23.55(2)，22.31(2)，21.37(0)，18.04(3)，12.81(2)，10.38(2)；

MS HRES value of calculation C ₂₇H ₃₆O ₃D ₆M+420.3511

Measured value M+420.3524

Embodiment 49

1 α, 25-dihydroxy-16-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols

At-78 ℃ to the (1S that stirred; 5R)-1; 5-two-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-2-methylene-cyclohexane extraction (536mg; 0.92mmol) in the solution of oxolane (7mL), add n-BuLi (0.58mL, 0.93mmol).Stirred the gained mixture 15 minutes, dropwise add (3aR, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (170mg, 0.46mmol) solution in oxolane (2mL).Stirred this reactant mixture 3.5 hours at-72 ℃, with hexane (35mL) dilution, (30mL) washs and uses Na with saline ₂SO ₄Dry.Residue behind the evaporating solvent (725mg) is through FC (15g, the solution of 5%AcOEt in hexane) purification obtains 1 α, 3 β-two (tert-butyl group-dimethyl-silanyloxy base)-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols (302mg, 041mmol).Under the room temperature to 1 α, 3 β-two (tert-butyl group-dimethyl-silanyloxy base)-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols (302mg, 0.41mmol) the middle tetrabutylammonium (4mL that adds, 4mmol, the 1M solution in THF).Stirred this mixture 15 hours, with AcOEt (25mL) dilution, water (5 * 20mL), saline (20mL) washs and uses Na ₂SO ₄Dry.Residue behind the evaporating solvent (280mg) obtains title compound (160mg, 0.37mmol, 80%) through FC (15g, 50%AcOEt solution and the AcOEt in hexane) purification.

[α] ²⁹ _D＝+15.3c 0.34，EtOH

UVλmax(EtOH)：207nm(ε17011)，264nm(ε15067)；

¹H NMR(CDCl ₃)：6.37(1H，d，J＝11.3Hz)，6.09(1H，d，J＝11.3Hz)，5.33(2H，m)，5.01(1H，s)，4.44(1H，m)，4.23(1H，m)，2.80(1H，dd，J＝11.9，3.2Hz)，2.60(1H，dd，J＝13.2，3.2Hz)，2.38-1.08(20H，m)，0.79(3H，s)，0.66-0.24(4H，m)；

¹³C NMR(CDCl ₃)：156.97(0)，147.53(0)，142.41(0)，132.94(0)，124.83(1)，124.68(1)，117.14(1)，111.60(2)，70.82(0)，70.71(1)，66.88(1)，59.55(1)，50.30(0)，45.23(2)，43.79(2)，42.90(2)，38.18(2)，35.64(2)，29.19(2)，28.71(2)，23.63(2)，22.30(2)，21.36(0)，17.91(3)，12.82(2)，10.39(2)；

MS HRES value of calculation C ₂₈H ₃₆O ₃D ₆M+432.3510

Measured value M+432.3517

Embodiment 50

1 α-fluoro-25-hydroxyl-16-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferols

At-78 ℃ to the (1S that stirred; 5R)-1-((tert-butyl group dimethyl) silanyloxy base)-3-[2-(diphenylphosphine acyl group)-second-(Z)-subunit]-5-fluoro-2-methylene-cyclohexane extraction (433mg; 0.92mmol) in the solution of oxolane (7mL), add n-BuLi (0.58mL, 0.93mmol).Stirred the gained mixture 15 minutes, dropwise add (3aR, 7aR)-7a-methyl isophthalic acid-[1-(5,5,5-three deuterium generation-4-three deuterium acute pyogenic infection of nails bases-4-TMS oxygen base-amyl group)-cyclopropyl]-3a, 4,5,6,7,7a-six hydrogen-3H-indenes-4-ketone (170mg, 0.46mmol) solution in oxolane (2mL).Stirred this reactant mixture 3.5 hours at-72 ℃, with hexane (25mL) dilution, (20mL) washs and uses Na with saline ₂SO ₄Dry.Residue behind the evaporating solvent (580mg) is through FC (15g, the solution of 10%AcOEt in hexane) purification, obtain the 1 α-tert-butyl group-dimethyl-silanyloxy base-3 β-fluoro-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26, and 27-six deuterium generation-cholecalciferols (260mg, 0.42mmol).

Under the room temperature to 1 α that the obtains-tert-butyl group-dimethyl-silanyloxy base-3 β-fluoro-25-TMS Oxy-1 6-alkene-20-cyclopropyl-26,27-six deuterium generation-cholecalciferol (260mg, 0.42mmol) the middle tetrabutylammonium (4mL, 4mmol, the 1M solution in THF) that adds.Stirred this mixture 15 hours, with AcOEt (25mL) dilution, water (5 * 20mL), saline (20mL) washs and uses Na ₂SO ₄Dry.Residue behind the evaporating solvent (260mg) obtains title compound (140mg, 0.32mmol, 70%) through FC (10g, 30%, the solution of 50%AcOEt in hexane) purification.

[α] ³⁰ _D＝+30.0c 0.30，EtOH

UVλmax(EtOH)：243nm(ε12254)，265nm(ε12144)；

¹H NMR(CDCl ₃)：6.40(1H，d，J＝11.3Hz)，6.10(1H，d，J＝11.1Hz)，5.39(1H，s)，5.34(1H，m)，5.13(1H，dm，J＝50Hz)，5.11(1H，s)，4.23(1H，m)，2.80(1H，m)，2.63(1H，m)，2.38-1.08(19H，m)，0.80(3H，s)，0.66-0.24(4H，m)；

¹³C NMR(CDCl ₃)：156.92(0)，143.06(0，d，J＝17Hz)，142.78(0)，131.49(0)，125.48(1)，124.71(1)，117.16(1)，114.67(2，d，J＝10Hz)，91.47(1，d，J＝172Hz)，70.83(0)，66.58(1，d，J＝6Hz)，59.55(1)，50.35(0)，45.00(2)，43.80(2)，40.79(2，d，J＝20Hz)，38.20(2)，35.68(2)，29.15(2)，28.74(2)，23.64(2)，22.32(2)，20.79(0)，17.96(3)，12.81(2)，10.41(2)；

MS HRES value of calculation C ₂₈H ₃₅FO ₂D ₆M+Na 457.3359

Measured value M+Na 457.3360

Biology embodiment

Biology, embodiment 1

Method:

Animal

For all tests, use female BALB/c mouse (20g; Charles River BreedingLaboratories).All mices all remain under the status of criterion, arbitrarily get food and drinking-water with this understanding, according to the official of stable breeding regulation keep 12 hours the daytime-circulation at night.

The mouse test model that adhesion forms

Employing comes adhesion (the Sulaiman H of inducing mouse based on the experimental program of the method for Sulaiman and colleague's foundation thereof, Gabellag, Davis C, Mutsaers SE, Boulos P, Laurent GJ, Herrick SE:Growth of nerve fibres into murine peritoneal adhesions.JPathol 2000,192:396-403).In brief, mice is anaesthetized by the mixture that sucks isoflurane and oxygen, with its by stomach wall and peritoneum along midline incision.On normal place, promptly scrape 30 times with knife blade and cause wound at the side direction 0.5cm place, center (6mm diameter and 1mm are dark) apart from midline incision of left side stomach wall.Peel off caecum and after pouring into 0.9% Sterile Saline first, scrape 30 times with knife blade in its side direction.With latter two wound surface by 2 horizontal mattress suture (8/0Ethilon apart from 1cm are set; Ethicon, Berkshire, Britain) and approaching.Midline incision divides two-layer the stitching; Hunter's line adopts continuously and sews up, and skin seals with michel suture clip (Aesculap, Tuttlingen Germany).(Enantone Takeida) verifies this model, and it is injected with 1mg/kg in operation the last week with GnRH agonist leuprorelin acetate.Generally animal was put to death at the 7th day, and the reduction of its adhesion scoring is assessed.

In order to estimate vitamin D compounds to the influence that adhesion forms, in 10 animals, induce peritoneal adhesion, described animal has been randomized to either in the experimental group of accepting vitamin D compounds or solvent.In initial research, the compounds X of peritoneal injection 200ug/kg of accepting 0.1-ml the animal (n=5) of operation experimental group on the same day in saline solution or only inject solvent (saline) (n=5), 4 day subsequently every day oral administration (compounds X, 100ug/kg in miglyol solution or only accept the miglyol solvent).Second experiment carried out with a treated animal (n=5), and it accepted the solution of chemical compound Y in saline of peritoneal injection 6ug/kg of 0.1-ml, oral administration 4 day subsequently every day (solution of 3ug/kg in miglyol) same day in operation.Control animal (n=5) is only used solvent (according to route of administration, being miglyol or saline) similarly.The 3rd experiment is designed to the effect of comparison calcitriol.In brief, 28 animals are used to experiment, it is assigned randomly in four different groups: solvent is (according to route of administration, be miglyol or saline) (n=13), compounds X peritoneal injection 200ug/kg is also subsequently with MTD oral medication three days (n=5), chemical compound Y peritoneal injection 30ug/kg is also subsequently with MTD oral medication three days (n=5), and calcitriol peritoneal injection 0.6ug/kg is also subsequently with MTD oral medication three days (n=5).All animals were condemned to death in the time of 7 days, to establish blind mode adhesion were carried out quantitatively.According to number, length and the intensity of formed adhesion, give the adhesion scoring to every animal.Also measure the millimeter that sticks to the caecum on the peritoneum.

The colorimetric determination of serum calcium level

According to the method for standard method being carried out minor alteration, with calcium drying-fast measuring test kit (Sentinel diagnostics, Milan, Italy) measure serum calcium: 10ul serum, standard solution or water are joined in the detectable of the reconstruct of 100ul on 96 orifice plates, hatched 5 minutes, subsequently at room temperature in the 550nm reading.Being operating as of standard substance is quadruplicate, and blank (water) is duplicate, and sample is triplicate.

The result:

Use the Balb/c mice to induce the postoperative intestinal adhesion of caecum wear model.Performed the operation back 4 hours, to the compounds X of using a 200ug/kg in the mouse peritoneum or solvent is only arranged, then 4 days oral once a day 100ug/kg.Put to death mice at the 7th day, open its abdominal part, check the existence of adhesion.Measure the length and the intensity of the adhesion of every place, and be expressed as the scoring of every solitary animal.Fig. 1 shows that the administration of compounds X significantly reduces total adhesion scoring.

Use the Balb/c mice to induce the postoperative intestinal adhesion of caecum wear model.Performed the operation back 4 hours, to the chemical compound Y that uses a 6ug/kg in the mouse peritoneum or solvent is only arranged, then 4 days oral once a day 3ug/kg.Put to death mice at the 7th day, open its abdominal part, check the existence of adhesion.Measure the length and the intensity of the adhesion of every place, and be expressed as the scoring of every solitary animal.Fig. 2 shows that the administration of chemical compound Y significantly reduces total adhesion scoring.

Use the Balb/c mice to induce the postoperative intestinal adhesion of caecum wear model.Performed the operation back 4 hours, to use a solvent in the mouse peritoneum or use a 200ug/kg compounds X, use a 30ug/kg chemical compound Y, use the calcitriol of a 0.6ug/kg, next 4 days once a day by MTD oral administration (be respectively 100,3,0.3ug/kg).Put to death mice at the 7th day, open its abdominal part, check the existence of adhesion.Measure the length and the intensity of the adhesion of every place, and be expressed as the scoring of every solitary animal.Perhaps measure the caecum length (mm) that adheres to peritoneum.Adopt Bang Fulangni multiple comparisons check carrying out statistical analysis by variance analysis.Fig. 3 has shown that compounds X contrasts the effect compared with calcitriol with miglyol with chemical compound Y.The difference of accepting between the animal of the animal of vitamin D compounds and solvent group is significant statistically.

From the animal of the described experiment of Fig. 3, obtain serum and measure the level of calcium.Fig. 4 has shown the calcium level in these experiments.In the administration group of compounds X this be provided with have down slight blood calcium too high, other animal groups all has normal serum calcium level.

Use CD1 mice is checked the serum calcium level after intraperitoneal is used the chemical compound Y of various dose.Second treated animal is accepted intraperitoneal (various dose) administration and with MTD (3ug/kg) oral administration 3 days.After the administration 24 hours the last time, measure serum calcium level.Fig. 5 shows, observes and adopts this therapeutic scheme not have the too high effect of blood calcium.

Used caecum wearing and tearing mouse model uses GnRH agonist leuprorelin acetate (Enantone Takeda) verifies, described medicine is injected with 1mg/kg in operation the last week in Fig. 1,2 and 3 experiment.Put to death animal at the 7th day routinely, measure total adhesion scoring, as shown in Figure 6.Observing scoring has the reduction of significance,statistical.

In a word, the result shows vitamin D compounds, and for example compounds X, chemical compound Y and calcitriol are being effective aspect the incidence rate of the peritoneal adhesion that reduces mouse model and/or the seriousness.

Biology, embodiment 2

Chemical compound Y is to the effect of fibrinolytic approach

Method:

3T3-L1 cell that will converge and following chemical compound overnight incubation: TGF-β 1 5ng/ml, chemical compound Y are 10 ^-6, 10 ^-7, 10 ^-8With 10 ^-9M.After removing supernatant, the fibrinolytic buffer that will comprise 3 μ M Fibrinogens and 100nM plasminogen (" BM ") adds each hole.Induce fibrin clot by adding the 20nM thrombin.Plank is hatched under 37 ℃, determines the density of grumeleuse by the optical density under the mensuration 405nm.The result is expressed as on different time points with the relative fibrin clot density of untreated cell as the standard gained.

The result:

The results are shown in Fig. 7.Chemical compound Y with dose-dependent mode accelerating fibers albumen grumeleuse by the dissolving of l cell.

Biology, embodiment 3

Chemical compound Y is to the effect of fibrinolytic approach

Method:

People's mesothelial cell (LP9, Cornell University) is incubated in 96 orifice plates of the chemical compound Y that has various dose.In the time of 48 hours, collect supernatant, measure the output of tPA and PAI-1 by ELISA.Calculate the ratio of tPA/PAI-1.Carry out statistical analysis by the variance analysis check.

The result:

The results are shown in Fig. 8.The ratio of tPA/PAI-1 has illustrated the rise of fibrinolytic action activity owing to chemical compound Y increases people's mesothelial cell's processing.

Biology, embodiment 4

Intraperitoneal single administration chemical compound Y-serum calcium level

Method:

To chemical compound Y or the calcitriol in aseptic salt solution of female BALB/c mouse intraperitoneal with various dose injection 100mL, described solution contains 0.1% tween 20,0.1% ethanol.Collect blood at two time points, measure serum calcium level.

The result:

The results are shown in Fig. 9.Observing chemical compound Y has the too high phenomenon of of short duration blood calcium under high dose (300mg/kg), and calcitriol has induced more remarkable and persistent blood calcium too high when intraperitoneal is used back 16 and 24 hours.

Biology, embodiment 5

The mice postoperative intestinal adhesion model of dose response effect research-caecum peritoneum scratch and stitching

Method:

The chemical compound Y of check various dose in the mice postoperative intestinal adhesion model of CPSS (scratch of caecum peritoneum and stitching).When operation finished, animal was handled with the solution of chemical compound Y in the 100mL Sterile Saline of peritoneal injection 30-100-300ug/kg, and described solution contains 0.1% tween 20,0.1% ethanol.Animal was put to death after two weeks, and estimated its peritoneal adhesion situation.Relatively four meansigma methodss that group is marked are in position investigated the animal that is subject to processing and are compared the reduction percentage rate of the meansigma methods of scoring in position with the solvent group.

The result:

The results are shown in Figure 10.Chemical compound Y reduces the formation of Ceco-peritoneal adhesion in dose-dependent mode.

Biology, embodiment 6

The rabbit postoperative intestinal adhesion model at dose response effect research-double uterus angle

Method:

The generality of double uterus angle rabbit model is described (DUH)

Scheme:

Animal: 28 female New Zealand white rabbits, 2.4-2.7kg, (Norco CA), isolated 2 days before use at least available from Irish Farms.Before beginning operation, 7 rabbits are assigned randomly in 4 processed group.Rabbit is housed in 12: 12 light: dark circulation and is arbitrarily got food and drinking-water down.

The double uterus angle model: to rabbit intramuscular injection 55mg/kg ketalar and 5mg/kg xylazine (Rompum) and anaesthetize.After being ready to aseptic operation, carry out the center line laparotomy ventrotomy.Take out cornua uteri, cause damage in the serosa surface friction up to petechial hemorrhage occurring with gauze.Induce the ischemia of two cornua uteris by the blood supply of blocking-up collateral branch.The remaining blood supply of cornua uteri relies on Utero-vaginal artery ascending branch to supply with.One of the dosage of the animals received 25mL solvent that is subject to processing (lactated Ringer solution contains 0.1% polysorbas20,0.1% isopropyl alcohol) or solvent and two kinds of chemical compound Y (30 or 300 μ g/kg).Another treated animal only undergos surgery.Then the angle is put back to its normal position of dissecting, center line is sewed up with 3-0 Vicryl.Animal is weighed before operation He before the postmortem.

After 7 days, put to death animal and measure the area percentage that sticks to various structural cornua uteris.In addition, use following system that the fastness of adhesion is marked:

0=does not have adhesion

A little less than the 1=, the adhesion that is easy to dissect

The medium adhesion of 2=; Can not dissect, not tear organ

The dense adhesion of 3=; Can not dissect, when removing, can tear organ

In addition, above-mentioned data are all taken into account, given overall score every rabbit.Use following marking system:

The adhesion scoring	Describe
The adhesion scoring	Describe	0	No adhesion
0.5	Gently, thin pelvis adhesion, only comprise an organ, the little adhesion in 1 or 2 places is only arranged usually	0	No adhesion
0.5		1.0	Gently, thin adhesion, expansion, but broader a little than 0.5
1.5	More tough and tensile a little and broader than grade 1	1.0
1.5	More tough and tensile a little and broader than grade 1	2.0	More tough and tensile adhesion, broad slightly, cornua uteri has the adhesion with intestinal and bladder usually
2.5	Except adhesion usually any position all quite well and broader, identical with 2	2.0
2.5		3.0	The more tough and tensile adhesion than 2, two angles all adhere to each other with intestinal and bladder, and the uterus can be done some and move
3.5	Identical with 3, but adhesion is broad and more tough and tensile slightly	3.0
3.5		4.0	Serious adhesion, two angles all adhere to each other with intestinal and bladder, can't not move if do not tear adhesion part uterus

By two independently the observer rabbit is marked, described observer for aforesaid animal handle should be established blind.If have different opinions, then adopt higher scoring for the mark that single animal gave.

The result:

The results are shown in Figure 11.Chemical compound Y has reduced the formation (for two kinds of dosage and two kinds of contrasts comparatively speaking, P＜0.001) of adhesion significantly than solvent group under two kinds of dosage.Do not find that when postmortem peritoneum inflammation, weight saving or blood calcium are too high.

Biology, embodiment 7

Chemical compound Y is to the effect of the serum calcium level of DUH rabbit model animal

Method:

Before operation, before operation back 24 hours and the postmortem, the blood that extracts 1mL to produce serum, is used for measuring serum calcium level in the reddish tone test tube.Make the blood clotting in bulk,, measure serum calcium by centrifugal collection serum.

The result:

The results are shown in Figure 12.Under three time points, two dosage, all do not observe the too high sign of blood calcium.

Biology, embodiment 8

Possible Study on Damage to the mouse model organization healing

Method:

Use the holostrome wound of a 1cm diameter of masterplate labelling, will organize to be cut to film water with dissecting scissors and tweezers and to put down.Draw the limit of wound with the thin film of spike and measure wound healing.The rate representation of wound healing is the percentage ratio of residual area.Every group of 5 nude mices, every day oral 3mg/kg chemical compound Y, one the week 5 times.Wound healing curve and the V50 (half of wound healing time) that uses Boltzmann equation calculated.Between two sets of curves, do not find significant difference on the statistics.

Mesothelial cell's (Connell cell bank) of people is cultivated on 96 orifice plates of the chemical compound Y that has various dose.In the time of 48 hours, collect supernatant, measure the output of VEGF and TGF-b by ELISA.Undertaken quantitatively by the number of fluorimetry living cells.

The result:

The results are shown in Figure 13 and Figure 14.

The result shows that chemical compound Y does not delay the healing (Figure 13) of wound in the holostrome mouse model.Chemical compound Y does not influence the output of VEGF and TGF-b to people's mesothelial cell's treatment, and these factors are for promoting that wound healing is important (Figure 14).

Biology, embodiment 9

To mice because the research of the mortality rate risk due to infect strengthening

Method:

Carry out CLP (caecum ligation and perforation) with the syringe needle of 23G and the caecum ligation of 50-70%.At operation intraperitoneal administered compound Y 30mg/kg on the same day.Twice inspection every day mortality rate.Every group is used 10 C57/BL6 mices.

The result:

The results are shown in Figure 15.Adopt sequence check to come the comparison survival curve, between the mice of solvent and chemical compound Y processing, do not demonstrate significant difference on the statistics.This confirmed chemical compound Y with because the risk that the mortality rate of bacterial infection due to strengthening raises does not have relatedly.

Biology, embodiment 10

The effectiveness of comparing with lazaroids with icodextrin

Use the result of chemical compound Y gained to compare with the result who uses icodextrin and lazaroids gained.The results are shown in Figure 16 and 17.The result shows chemical compound Y aspect the adhesion formation of prevention DUH rabbit model, compares with the research of lazaroids (Figure 17) with former icodextrin (Figure 16) to have suitable effectiveness.The data of icodextrin are from people such as SJS Verco, Human Reproduction, 15 (8) 1764-1772 (2000).The data of lazaroids are from people such as KE Rodgers, HumanReproduction, 13 (9) 2443-2451 (1998).Carry out testing identical laboratory with the test of its chemical compound Y that compares with people such as Rodgers.

The general introduction of biological results

Can reach a conclusion from described result, vitamin D compounds for example calcitriol, compounds X and particularly chemical compound Y is effective in the adhesion that reduces animal model forms, and wound healing is not had ill effect, can not raise because the mortality rate due to the infection enhancing.

Abbreviation

The SFM=serum-free medium

The i.p.=intraperitoneal

" comprise "

In whole description and claims subsequently, unless context has requirement in addition, otherwise word " comprises " or its variant for example " comprises/comprise " and should be understood to comprise described integral body or step or the whole group or the group of step, but does not get rid of any other integral body or step or the whole group or group of step.

Be incorporated herein by reference

The content of all references of quoting among the application (comprising the patent of list of references, promulgation, disclosed patent application and patent application co-pending) integral body clearly is incorporated herein by reference.

Equivalents

Those skilled in the art will recognize that or can determine and utilize not transnormal experimental technique, can obtain a lot of equivalents of the specific embodiments of invention described herein.This class equivalents also is covered by in the following claim.

Claims

1. the method for a Film with Preventing Adhesion, it comprises the use vitamin D compounds.

2. the method for Film with Preventing Adhesion in individuality, this method comprise vitamin D compounds from effective dose to its individuality of needs that use, so as in this individuality Film with Preventing Adhesion.

3. method as claimed in claim 2, it also comprises differentiates the individuality that needs Film with Preventing Adhesion.

4. as claim 2 or the described method of claim 3, it also comprises the step that obtains vitamin D compounds.

5. as each described method among the claim 2-4, individuality wherein is a mammal.

6. the method described in claim 5, individuality wherein is the people.

7. as each described method among the claim 1-6, wherein vitamin D compounds is configured to pharmaceutical composition with acceptable diluents or carrier.

Vitamin D compounds the preparation Film with Preventing Adhesion medicine in purposes.

9. comprise the pharmaceutical preparation of vitamin D compounds and pharmaceutically suitable carrier, it is used for Film with Preventing Adhesion.

10. comprise the pharmaceutical preparation of vitamin D compounds and pharmaceutically suitable carrier, it is packed with the description that is used for Film with Preventing Adhesion.

11. be used for the vitamin D compounds of Film with Preventing Adhesion.

12. comprise the medicine box of vitamin D compounds and description, thereby described description is about use described chemical compound Film with Preventing Adhesion in described patient to the patient who needs Film with Preventing Adhesion.

13. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-12, wherein vitamin D compounds in pharmaceutical preparation that separate or combination with second medicine that prevents and/or treats adhesion separately, successively or use simultaneously.

14. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-13, wherein said adhesion is a postoperative intestinal adhesion.

15. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-14, wherein said adhesion is a peritoneal adhesion.

16. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is chemical compound and pharmaceutically acceptable ester, salt and the prodrug of following formula:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

X ₁And X ₂Be independently of one another H or=CH ₂, condition is X ₁And X ₂Be not simultaneously=CH ₂

R ₁And R ₂Be OH, OC (O) C independently of one another ₁-C ₄Alkyl, OC (O) hydroxy alkyl, OROC (O) haloalkyl, OAc;

R ₆And R ₇Be C independently of one another _1-4Alkyl or haloalkyl; And

R ₈Be H ,-COC ₁-C ₄Alkyl ,-the CO hydroxy alkyl or-the CO haloalkyl.

17. purposes as claimed in claim 16, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OH or OC (O) C ₁-C ₄Alkyl.

18. purposes as claimed in claim 17, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OAc.

19. purposes as claimed in claim 17, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OH.

20. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 16-19 ₁Be=CH ₂And X ₂Be H.

21. as each described purposes, method, preparation, chemical compound or medicine box, wherein A among the claim 16-20 ₁Be singly-bound and A ₂It is singly-bound.

22. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 16-21 ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl.

23. purposes as claimed in claim 22, method, preparation, chemical compound or medicine box, wherein R ₃And R ₄With C ₂₀Form cyclopropyl together.

24. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 16-23 ₅Be hydrogen.

25. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 16-24 ₆And R ₇Be C independently of one another _1-4Alkyl.

26. purposes as claimed in claim 25, method, preparation, chemical compound or medicine box, wherein R ₆And R ₇Be methyl independently of one another.

27. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 16-26 ₈Be H.

28. purposes as claimed in claim 16, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OH or OC (O) C ₁-C ₄Alkyl, X ₁Be=CH ₂And X ₂Be H, A ₁Be singly-bound, A ₂Be singly-bound, R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl, R ₅Be hydrogen, R ₆And R ₇Be C independently of one another _1-4Alkyl, and R ₈Be H.

29. purposes as claimed in claim 28, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Be OH or OAc, R ₃And R ₄With C ₂₀Form cyclopropyl together, and R ₆And R ₇Each is methyl naturally.

30. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XVI) chemical compound:

Wherein:

X is H ₂Or CH ₂

R ₁Be hydrogen, hydroxyl or fluorine;

R ₂Be hydrogen or methyl;

R ₄Be methyl, ethyl or trifluoromethyl;

R ₅Be methyl, ethyl or trifluoromethyl;

A is singly-bound or two key;

B is the two keys of singly-bound, E-, the two keys of Z-or three key.

31. purposes as claimed in claim 30, method, preparation, chemical compound or medicine box, wherein R ₄And R ₅Be methyl or ethyl independently of one another.

32. purposes as claimed in claim 30, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds are 1-α-fluoro-25-hydroxyls-16,23E-diene-26, and 27-pair of high-20-table-cholecalciferol, it has following formula:

33. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (IV) chemical compound:

Wherein:

A is singly-bound or two key;

A ₂Be singly-bound, two key or three key;

A ₃Be singly-bound or two key;

R ₅Be H ₂Or oxygen, R ₅Also can represent hydrogen or can not exist;

R ₃Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, and

R ₄Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl.

34. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is the formula V chemical compound:

Wherein:

A is singly-bound or two key;

A ₂Be singly-bound, two key or three key;

A ₃Be singly-bound or two key;

R ₅Be H ₂Or oxygen, R ₅Also can represent hydrogen or can not exist;

R ₃Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, and

R ₄Be C ₁-C ₄Alkyl, hydroxy alkyl haloalkyl.

35. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (VI) chemical compound:

Wherein:

X ₁Be H ₂Or CH ₂

A ₂Be singly-bound, two key or three key;

R ₃Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl;

R ₄Be C ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl;

And C ₂₀Configuration be R or S.

36. purposes as claimed in claim 35, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds is 1, and 25-dihydroxy-21-(3-hydroxy-3-methyl butyl)-19-falls-cholecalciferol, and it has following formula:

37. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (VII) chemical compound:

Wherein:

A is singly-bound or two key;

R ₁And R ₂Be hydrogen, alkyl independently of one another;

R ₃And R ₄Be alkyl independently of one another, and

X is hydroxyl or fluorine.

38. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (VIII) chemical compound:

Wherein:

R ₁And R ₂Be hydrogen or alkyl independently of one another;

R ₃It is alkyl;

R ₄It is alkyl; And

X is hydroxyl or fluorine.

39. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (IX) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

C ₂₀Configuration be R or S;

X ₁Be H ₂Or CH ₂

40. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein A ₁It is singly-bound.

41. as claim 39 or 40 described purposes, method, preparation, chemical compound or medicine box, wherein A ₂It is singly-bound.

42. as claim 39 or 40 described purposes, method, preparation, chemical compound or medicine box, wherein A ₂It is three key.

43. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 39-42 ₁, R ₂, R ₃And R ₄Be methyl, ethyl, C independently of one another ₁-C ₄Deuterium substituted alkyl or haloalkyl.

44. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 39-43 ₅It is hydroxyl.

45. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 39-44 ₆And R ₇Be hydroxyl or OC (O) C independently of one another ₁-C ₄Alkyl.

46. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 39-45 ₁Be H ₂

47. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 39-45 ₁Be CH ₂

48. as each described purposes, method, preparation, chemical compound or medicine box among the claim 39-47, wherein Z be hydrogen or=O.

49. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein Z is a hydrogen, at least one R ₁And R ₂Be C ₁-C ₄Deuterium substituted alkyl and at least one R ₃And R ₄It is haloalkyl.

50. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein Z is a hydrogen, at least one R ₁And R ₂Be haloalkyl and at least one R ₃And R ₄Be C ₁-C ₄The deuterium substituted alkyl.

51. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein Z be-OH ,=O ,-SH or-NH ₂And X ₁Be CH ₂

52. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein Z be-OH ,=O ,-SH or-NH ₂X ₁Be H ₂And C ₂₀Configuration be S.

53. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein Z be=O ,-SH or-NH ₂X ₁Be H ₂And C ₂₀Configuration be R.

54. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is-OH.

55. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is=O.

56. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be H ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; C ₂₀Configuration be S; And Z is-OH.

57. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be H ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is=O.

58. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be H ₂A ₂It is three key; R ₁And R ₂Each is C naturally ₁-C ₄The deuterium substituted alkyl; R ₃And R ₄Each is haloalkyl naturally; And Z is a hydrogen.

60. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein X ₁Be CH ₂A ₂It is three key; R ₁And R ₂Each is C naturally ₁-C ₄The deuterium substituted alkyl; R ₃And R ₄Each is haloalkyl naturally; And Z is a hydrogen.

61. purposes as claimed in claim 39, method, preparation, chemical compound or medicine box, wherein R ₁And R ₂Each is deuterium acute pyogenic infection of nails base and R naturally ₃And R ₄Each is trifluoromethyl naturally.

62. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (X) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

X ₁Be H ₂Or CH ₂

A ₂Be singly-bound, two key or three key;

R ₁, R ₂, R ₃And R ₄Be C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl;

Z is-OH ,=O ,-NH ₂Or-SH;

And C ₂₀Configuration be R or S.

63. purposes as claimed in claim 62, method, preparation, chemical compound or medicine box, wherein X ₁Be CH ₂

64. as claim 62 or 63 described purposes, method, preparation, chemical compound or medicine box, wherein A ₂It is singly-bound.

65. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 62-64 ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another.

66. as each described purposes, method, preparation, chemical compound or medicine box among the claim 62-65, wherein Z is-OH.

67. purposes as claimed in claim 62, method, preparation, chemical compound or medicine box, wherein X ₁Be CH ₂A ₂It is singly-bound; R ₁, R ₂, R ₃And R ₄Be methyl or ethyl independently of one another; And Z is-OH.

68. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XI) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

R ₃And R ₄Be hydrogen, C independently of one another ₁-C ₄Alkyl, hydroxy alkyl or haloalkyl, perhaps R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl; And

R ₅And R ₆Be C independently of one another ₁-C ₄Alkyl or haloalkyl.

69. as the described purposes of claim 68, method, preparation, chemical compound or medicine box, wherein R ₃And R ₄Be hydrogen, C independently of one another ₁-C ₄Alkyl is perhaps with C ₂₀Form C together ₃-C ₆Cycloalkyl.

70. as the described purposes of claim 69, method, preparation, chemical compound or medicine box, wherein R ₃Be hydrogen and R ₄Be C ₁-C ₄Alkyl.

71. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 68-70 ₅And R ₆Be C independently of one another ₁-C ₄Alkyl.

72. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 68-70 ₅And R ₆Be haloalkyl independently of one another.

73. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 68-70 ₅And R ₆Be methyl, ethyl, methyl fluoride or trifluoromethyl independently of one another.

74. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 68-73 ₁And X ₂Each is H naturally ₂

75. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 68-74 ₁And R ₂Be hydroxyl or OC (O) C independently of one another ₁-C ₄Alkyl.

76. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is that-20 (S)-1-α, 25-hydroxy-vitamin D fall in 2-methylene-19- ₃:

77. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XII) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₁And R ₂Be H, OC (O) C independently of one another ₁-C ₄Alkyl, OC (O) hydroxy alkyl, OC (O) haloalkyl;

R ₆And R ₇Be C independently of one another _1-4Alkyl or haloalkyl; And

R ₈Be H ,-COC ₁-C ₄Alkyl ,-the CO hydroxy alkyl or-the CO haloalkyl.

78. as the described purposes of claim 77, method, preparation, chemical compound or medicine box, wherein R ₃And R ₄With C ₂₀Form C together ₃-C ₆Cycloalkyl.

79. as the described purposes of claim 77, method, preparation, chemical compound or medicine box, wherein R ₃Be hydrogen and R ₄Be C ₁-C ₄Alkyl.

80. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 77-79 ₆And R ₇Be C independently of one another _1-4Alkyl or haloalkyl.

81. as the described purposes of claim 80, method, preparation, chemical compound or medicine box, wherein R ₆And R ₇Be haloalkyl independently of one another.

82. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 77-81 ₈Be H or-COC ₁-C ₄Alkyl.

83. as each described purposes, method, preparation, chemical compound or medicine box, wherein A among the claim 77-82 ₁Be singly-bound and A ₂Be two keys of singly-bound, E or Z or three key.

84. as each described purposes, method, preparation, chemical compound or medicine box, wherein A among the claim 77-82 ₁Be two keys and A ₂Be two keys of singly-bound, E or Z or three key.

85. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 77-84 ₁And X ₂Each is H naturally.

86. as each described purposes, method, preparation, chemical compound or medicine box, wherein X among the claim 77-84 ₁Be CH ₂And X ₂Be H ₂

87. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 77-86 ₁And R ₂All represent OAc.

88. as each described purposes, method, preparation, chemical compound or medicine box, wherein R among the claim 77-87 ₅Be hydrogen.

89. as the described purposes of claim 77, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds is formula (XIV) chemical compound:

90. as the described purposes of claim 77, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds is formula (XV) chemical compound:

91. as the described purposes of claim 90, method, preparation, chemical compound or medicine box, wherein X ₁Be=CH ₂And X ₂Be H ₂

92. as the described purposes of claim 91, method, preparation, chemical compound or medicine box, wherein A ₁Be singly-bound, A ₂Be three key, R ₈Be H or C (O) CH ₃, and R ₆And R ₇It is alkyl.

93. as the described purposes of claim 91, method, preparation, chemical compound or medicine box, wherein A ₁Be singly-bound, A ₂Be singly-bound, R ₈Be H or C (O) CH ₃, and R ₆And R ₇It is alkyl.

94. as the described purposes of claim 91, method, preparation, chemical compound or medicine box, wherein A ₁Be two keys, A ₂Be singly-bound, R ₈Be H or C (O) CH ₃, and R ₆And R ₇It is alkyl.

95. as the described purposes of claim 90, method, preparation, chemical compound or medicine box, wherein X ₁And X ₂Each is H naturally ₂

96. as the described purposes of claim 95, method, preparation, chemical compound or medicine box, wherein A ₁Be singly-bound, A ₂Be three key, R ₈Be H or C (O) CH ₃, and R ₆And R ₇Be alkyl or haloalkyl.

97. as the described purposes of claim 95, method, preparation, chemical compound or medicine box, wherein A ₁Be singly-bound, A ₂Be two keys, R ₈Be H or C (O) CH ₃, R ₆And R ₇It is haloalkyl.

98. as the described purposes of claim 95, method, preparation, chemical compound or medicine box, wherein A ₁Be two keys, A ₂Be singly-bound, R ₈Be H or C (O) CH ₃, R ₆And R ₇It is alkyl.

99. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XVII) chemical compound:

Wherein:

B is singly-bound, two key or three key;

X ₁And X ₂Be H independently of one another ₂Or CH ₂, condition is X ₁And X ₂Not all be CH ₂And

R ₄And R ₅Be alkyl or haloalkyl independently of one another.

100. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XVIII) chemical compound:

A wherein ₁Be two keys or singly-bound;

A ₂Be three key, two key or singly-bound;

X ₁Be=CH ₂Or H ₂

X ₂Be H ₂

R ₆And R ₇Be alkyl or haloalkyl independently of one another; And

R ₈Be H or C (O) CH ₃

101. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XIX) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

R ₆And R ₇Be haloalkyl independently of one another; And

R ₈Be H, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl.

102. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XX) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₁Be singly-bound or two key;

A ₂Be singly-bound, two key or three key;

X ₁Be H ₂Or CH ₂

Y is an alkyl.

103. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein said vitamin D compounds is formula (XX-a) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₆Be hydroxyl, OC (O) alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl;

X ₁Be H ₂Or CH ₂

104. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein wherein said vitamin D compounds is formula (XX-b) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

105. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein wherein said vitamin D compounds is formula (XX-c) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

106. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein wherein said vitamin D compounds is formula (XX-d) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

107. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein wherein said vitamin D compounds is formula (XX-e) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

108. as the described purposes of claim 102, method, preparation, chemical compound or medicine box, wherein wherein said vitamin D compounds is formula (XX-f) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein:

A ₂Be singly-bound, two key or three key;

R ₅Be fluorine or hydroxyl;

X ₁Be H ₂Or CH ₂

109. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is formula (XXII) chemical compound and pharmaceutically useful ester, salt and prodrug:

Wherein: A is singly-bound or two key; B is singly-bound, two key or three key; X is H ₂Or CH ₂Y is hydroxyl, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl, OC (O) haloalkyl; Or halogen; Z is hydroxyl, OC (O) C ₁-C ₄Alkyl, OC (O) hydroxy alkyl or OC (O) haloalkyl.

110. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is to have 1 of following formula, 3-two-O-acetyl group-1, and 25-dihydroxy-20-cyclopropyl-cholecalciferol:

111. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said vitamin D compounds is to have 1 of following formula, 25-dihydroxy-20,21, and 28-cyclopropyl-cholecalciferol:

112. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-15, wherein said chemical compound is a calcitriol.

113. as each described purposes, method, preparation, chemical compound or medicine box among the claim 1-112, wherein said vitamin D compounds not with crosslinked composition or crosslinkable composition co-administered or common preparation, described composition reacts to each other in aqueous environments and forms three-dimensional substrate.