CN101880253A - Preparation method of paricalcitol - Google Patents

Preparation method of paricalcitol Download PDF

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CN101880253A
CN101880253A CN2009101364413A CN200910136441A CN101880253A CN 101880253 A CN101880253 A CN 101880253A CN 2009101364413 A CN2009101364413 A CN 2009101364413A CN 200910136441 A CN200910136441 A CN 200910136441A CN 101880253 A CN101880253 A CN 101880253A
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compound
hydroxyl
zemplar
preparation
silica
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CN101880253B (en
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李瀛
薛吉军
张宪恕
徐少军
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Chongqing Taihao Pharmaceutical Co Ltd
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Chongqing Taihao Pharmaceutical Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of paricalcitol, which is characterized in that after hydroxyl in the vitamin D2 is protected by p-toluenesulfonates, in the presence of alkali, intramolecular cyclization reaction happens in methanol to generate a compound 5; the compound 5 undergoes allylic oxidation and hydroxyl is protected to obtain a key intermediate 7; in the presence of ozone, the side chains and exocyclic terminal double bonds of the key intermediate 7 are cut off to obtain a compound 8; the primary hydroxyl in the compound 8 is selectively protected, a three-membered ring is opened in the presence of acid and then hydroxyl is protected to obtain a key intermediate 11; after the secondary hydroxyl in the key intermediate 11 is protected by sulphonate, a compound 12 is obtained through reduction by LiAlH4; a compound 13 is obtained after the compound 12 is subjected to Swern oxidation and carries out Wittig reaction with the compound 12 to obtain a compound 14; and the target compound can be obtained by removing the protective group in the compound 14. The reagents used in the method are simple and are convenient to operate, the reactions concerning regioselectivity and stereoselectivity are few, the route is shorter and 12 steps of reactions are carried out.

Description

The preparation method of Zemplar
Technical field
The present invention relates to the synthetic of a kind of compound, particularly relate to a kind of preparation method of Zemplar.
Background technology
Paricalcitol (activated vitamin D medicine, Zemplar) is the medicine that is used for prevention and treatment secondary hyperparathyroidism (SHPT), it demonstrates prevention and treats curative effect accepting III before dialysis and the transplantation and IV phase chronic renal disease (CKD) patient's SHPT, the most widely used SHPT prevention of dialysis patients and medicine have been become, by the Rat parathyroid hormone 1-34 (PTH) of oral administration reduction easily level, simultaneously blood calcium and serium inorganic phosphorus level are had minimum influence, and the PTH reduction is a critical index of SHPT treatment curative effect.The knot of Zemplar
Figure B2009101364413D0000011
The structure formula is referring to formula 1:1 Paricalcitol formula 1
Synthetic Zemplar mainly contains following two kinds of methods in the prior art:
Article one, route (US5281731, US5086191) adopted the strategy that converges to synthesize, wherein the six-ring fragment is from quinic acid, this compound is very expensive, in building-up process, also use as TMSCH2COOEt 1, the reagent that 1-thiocarbonyl diimidazole, Bu3SnH etc. are very expensive.Its other a slice is to be obtained by the VD2 oxidation, and it lacks Atom economy.The joint efficiency of last this connection of two and their connection product and side chain is all very low.The total reactions steps of this route is a lot.Detailed process is referring to formula 2.
Figure B2009101364413D0000021
Formula 2
The second route is long, and (WO2008053961 JP053392300), surpasses the reaction of 17 steps.Wherein, the Julia coupling alkylene yield of using when connecting side chain is low, uses very not environmental protection of Na-Hg; Several steps reaction of when exocyclic double bond is transformed, using, selectivity is not fine, as the bishydroxy reaction may the oxidation side chain two keys, or the like.Detailed process is referring to formula 3.
Figure B2009101364413D0000031
Formula 3
Summary of the invention
The objective of the invention is to, overcome the defective of the synthetic existence of existing Zemplar, and provide a kind of new handkerchief upright preparation method of solidifying alcohol, method agents useful for same of the present invention is simple, easy to operate, and relating to regioselectivity and stereoselective reaction seldom, route is shorter, the reaction of 12 steps.
The object of the invention to solve the technical problems realizes by the following technical solutions.The preparation method of a kind of Zemplar that proposes according to the present invention, said method comprising the steps of: a) at first the hydroxyl of vitamin D2 is obtained compound 4 with sulphonate protection, then under the effect of alkali, in methyl alcohol, compound 4 intramolecular cyclizations obtain compound 5, again compound 5 is carried out allylic oxidation, obtain compound 6; B) hydroxyl of compound 6 protected after, obtain compound 7, by optionally cutting off the outer terminal double link of ring in the compound 7 and two keys of side chain, and by obtaining diol compound 8 with the cancellation reaction, and then optionally protect the one-level hydroxyl in the compound 8 to obtain compound 9 with acyl group, the triatomic ring of opening under acidic conditions in 9 obtains glycol 10; C) utilize the sterically hindered difference of two hydroxyls in the compound 10 optionally to protect a hydroxyl to obtain compound 11 with silicon ether, and then with the another one hydroxyl in the sulphonate protection 11, and reduce with LiAlH4 and to slough sulphonate and ethanoyl obtains compound 12; D) after compound 12 obtains compound 13 by the Swern oxidation, with side chain 2 the Wittig reaction taking place and obtain compound 14, slough three protecting groups in the compound 14 at last, obtains the target compound Zemplar.
The object of the invention to solve the technical problems also can be applied to the following technical measures to achieve further.
The preparation method of aforesaid Zemplar, wherein, in the step b), the hydroxyl of described compound 6 can be protected with R1, obtains compound 7,
Figure B2009101364413D0000041
R1 can be an ethanoyl, benzoyl, tertiary butyl dimethyl-silicon, triethyl silicon or methoxyl methyl.
The preparation method of aforesaid Zemplar, outer terminal double link of the ring in the wherein said selective rhizotomy compound 7 and pendant double bonds can be undertaken by ozonization.
The preparation method of aforesaid Zemplar, the primary hydroxyl in the wherein said compound 8 obtains compound 9 with the R2 protection,
Figure B2009101364413D0000042
R2 can be the acetyl or benzoyl base.
The preparation method of aforesaid Zemplar, in the wherein said step c), a hydroxyl of 3 in the selective protection compound 10 is to obtain compound 11 with protecting group R3,
Figure B2009101364413D0000051
R3 can be trimethyl silicon based, and triethyl is silica-based, and tertiary butyl dimethyl is silica-based, triisopropylsilyl, the silica-based or benzoyl of tert-butyl diphenyl.
The preparation method of aforesaid Zemplar, wherein, the used sulphonate of hydroxyl in the protection compound 11 can be: methanesulfonates, p-toluenesulfonic esters, benzene sulfonate, closilate is to fluorobenzene sulphonate or triflate.
The preparation method of aforesaid Zemplar, wherein, the used reagent of sloughing in the compound 14 of protecting group can be protonic acid or Lewis acid.
The preparation method of aforesaid Zemplar, wherein said protonic acid can be a hydrochloric acid, sulfuric acid, tosic acid, camphorsulfonic acid or tosic acid pyridinium salt; Described Lewis acid can be BF 3, ZnI 2, ZrCl 4Or MgBr 2
The preparation method of aforesaid Zemplar, wherein, in the step d), the structural formula of described side chain 2 and compound 14 is as follows:
Figure B2009101364413D0000052
Side chain 2
Figure B2009101364413D0000053
The preparation method of aforesaid Zemplar, the protecting group R4 of wherein said side chain 2 and compound 14 can be a methoxymethyl, hydrogen, triethyl is silica-based or trimethyl silicon based.
The preparation method of aforesaid Zemplar, wherein, compound 11 can also obtain by following reaction formula from compound 9:
Figure B2009101364413D0000061
Wherein, R1 can be an ethanoyl, benzoyl, tertiary butyl dimethyl-silicon, triethyl silicon or methoxy first; R2 can be the acetyl or benzoyl base; R3 can be trimethyl silicon based, and triethyl is silica-based, and tertiary butyl dimethyl is silica-based, triisopropylsilyl, the silica-based or benzoyl of tert-butyl diphenyl.
By technique scheme, the unusual effect that the preparation method of Zemplar of the present invention has is: method agents useful for same of the present invention is simple, easy to operate, and relate to regioselectivity and stereoselective reaction seldom, route is shorter, only need the reaction of 12 steps, can obtain not by the end product of by-product contamination.
Above-mentioned explanation only is the general introduction of technical solution of the present invention, for can clearer understanding technique means of the present invention, and can be implemented according to the content of specification sheets, and for above-mentioned and other purposes, feature and advantage of the present invention can be become apparent, below especially exemplified by preferred embodiment, and conjunction with figs., be described in detail as follows.
Embodiment
Reach technique means and the effect that predetermined goal of the invention is taked for further setting forth the present invention, below in conjunction with accompanying drawing and preferred embodiment, its embodiment of preparation method, method, step, feature and the effect thereof of the Zemplar that foundation the present invention is proposed, describe in detail as after.
Method of the present invention is a starting raw material with the vitamin D2, and after having protected triatomic ring, the protection hydroxyl obtains compound 7,
R1 can be an ethanoyl, benzoyl, tertiary butyl dimethyl-silicon, triethyl silicon, methoxyl methyl.Compound 7 is the two keys on the outer and side chain with cutting ring of ozonization, reduce and obtain compound 8, and selective esterification obtains compound 9.
R2 can be an ethanoyl, benzoyl.
Compound 9 open loops obtain compound 10, and the selective protection hydroxyl obtains compound 11.
Figure B2009101364413D0000072
R3 can be trimethyl silicon based, and triethyl is silica-based, and tertiary butyl dimethyl is silica-based, triisopropylsilyl, and tert-butyl diphenyl is silica-based, benzoyl.
Reduce by sulphonate protection, LiAlH4 then and remove the hydroxyl that stays after exocyclic double bond cuts off.
Sulphonate herein can be expressed as:
Figure B2009101364413D0000073
R can be a methanesulfonates, p-toluenesulfonic esters, and benzene sulfonate, closilate is to fluorobenzene sulphonate, triflate.
The hydroxyl that compound 9 also can directly stay after cutting off by sulphonate protection, LiAlH4 reduction removing exocyclic double bond then; Open loop more then, the protection hydroxyl obtains compound 11.
Introduce new side chain 2 by the Wittig reaction again.
R4 can be a methoxymethyl, hydrogen, and triethyl is silica-based, and is trimethyl silicon based.
Its concrete reaction process is shown below: the starting raw material vitamin D2 is behind p-toluenesulfonic esters protection hydroxyl; under the effect of alkali; intramolecular cyclization reaction takes place in methyl alcohol generate compound 5; 5 through allylic oxidation; the protection of hydroxyl obtains key intermediate 7; under ozonization, 7 side chain and the outer terminal double link of ring are cut off and obtain compound 8.Compound 8 is optionally protected the one-level hydroxyl, opens triatomic ring under the effect of acid, then obtains key intermediate 11 carrying out hydroxyl protection.Secondary hydroxyl in 11 obtains compound 12 under the LiAlH4 reduction after the sulphonate protection.Compound 12 also can be by compound 9 directly after sulphonate protection, in the LiAlH4 reduction, and open loop then, protection is separated protection and is obtained compound 12.Compound 12 obtains 13,13 after through the Swern oxidations and with compound 2 the Wittig reaction takes place and obtain compound 14, and the protecting group of sloughing in 14 just can obtain target compound.Referring to formula 4.
Figure B2009101364413D0000082
Figure B2009101364413D0000091
Formula 4
In a specific embodiment of the present invention, its synthetic method is as follows:
A. getting Vitamin D2 is dissolved in the pyridine, stir down in batches 4-dimethylamino pyridine to Tosyl chloride that wherein adds 1 to 3 times of molar weight and catalytic amount, stirring is spent the night, after treating that raw material disappears, stir and slowly pour into reaction solution in the saturated sodium bicarbonate aqueous solution down, stirred extracted with diethyl ether, anhydrous sodium sulfate drying 30 minutes.After filtering evaporate to dryness, get intermediate 4.
B. get the first step product 4 and add dissolve with methanol, stir down to the NaHCO that wherein adds 5 to 50 times of molar weights 3, reflux 8h is behind the pressure reducing and steaming methyl alcohol, resistates is cooled to room temperature, adds ethyl acetate (2000ml) and stirs 20 minutes after-filtration, and solid washs with ethyl acetate, filtrate merge the back concentrate crude product 5, this crude product can obtain compound 5 with recrystallizing methanol.
C. get the CH that the second step crude product is dissolved in 15 to 50 times of quality 2Cl 2Among-the MeOH (1: 1), get the SeO of 0.5 to 2.0 times of molar weight of compound 5 2Add CH 2Cl 2-MeOH (1: 1,500ml), again to the toluene solution of the peroxy tert-butyl alcohol of 4 times of molar weights that wherein add compound 5, after the stirring at room reaction 3 hours, the solution of the product 5 in second step is slowly splashed into wherein (30min), after dripping off, continue stirring reaction 30min, to the excessive oxygenant of aqueous solution cancellation that wherein slowly adds sodium bisulfite, add back stirring reaction 1h, CH 2Cl 2Extraction merges organic phase, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates obtains compound 6 by purification by silica gel column chromatography.
D. get the 3rd step product 6 and be dissolved in CH 2Cl 2In, to the diisopropyl ethyl amine of 1.0 to 2.0 times of molar weights that wherein add compound 6, slowly to the protection reagent of 1.0 to 1.5 times of molar weights that wherein splash into compound 6, the stirring at room reaction is spent the night, and adds water then, behind the separatory, and water CH 2Cl 2Extraction merges organic phase, anhydrous sodium sulfate drying.After filtering evaporate to dryness, the resistates purification by silica gel column chromatography gets compound 7.
E. get the 4th step product 7 and be dissolved in CH 2Cl 2Among-the MeOH (1: 1), acetone-liquid nitrogen bath is cooled to-65 ℃, feeds ozone, stirs 1h, to wherein feeding argon gas 5 minutes, adds the NaBH of 4 times of molar weights of compound 7 4, rise to room temperature naturally, add saturated NH behind the 1h 4The cancellation of the Cl aqueous solution, CH 2Cl 2Extract three times, merge organic phase, anhydrous sodium sulfate drying, after the filtering and concentrating, resistates gets compound 8 with purification by silica gel column chromatography.
F. get the 5th step product 8 and be dissolved in CH 2Cl 2In, to the pyridine that wherein adds 1.5 to 3.0 times of molar weights, then, slowly to the acid anhydrides that wherein splashes into 1.0 to 1.5 times of molar weights, stirred overnight at room temperature adds the shrend reaction of going out, after two-phase is separated, and water CH 2Cl 2Extraction merges organic phase and washes with saturated common salt, anhydrous sodium sulfate drying, and after the filtering and concentrating, resistates obtains compound 9 with purification by silica gel column chromatography.
G. get the 6th step product 9 and be dissolved in DMSO and the acetic acid (3: 1), stir, heating, treat that raw material disappears after, reaction solution is poured in the frozen water into the saturated NaHCO of extracted with diethyl ether, organic phase 3The aqueous solution is washed, anhydrous sodium sulfate drying.Resistates obtains compound 10 with purification by silica gel column chromatography after filtering evaporate to dryness.
H. get above-mentioned the 7th step product 10 and be dissolved among the DMF, add imidazoles and TERT-BUTYL DIMETHYL CHLORO SILANE, stirring at room is reacted to raw material and is disappeared.Reaction solution is poured in the water, and extracted with diethyl ether merges organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates obtains flower compound 11 with purification by silica gel column chromatography.
I. above-mentioned gained compound 11 is dissolved in CH 2Cl 2In, to the methylsulfonyl chloride of the Et3N that wherein adds 1.0 to 5.0 times of molar weights and 1.0 to 2.0 times of molar weights, room temperature reaction was used CH after 10 hours under the Ar atmosphere 2Cl 2Extraction, drying, after concentrating, resistates is dissolved among the THF, ice-water bath cooling down, to wherein adding LiAlH4, room temperature reaction 3 hours adds the shrend reaction of going out, filtration is removed photoresist behind the body, the mother liquor ethyl acetate extraction, and after dry the concentrating, resistates obtains compound 12 with purification by silica gel column chromatography.
I. compound 9 is dissolved in CH 2Cl 2In, to the methylsulfonyl chloride of the Et3N that wherein adds 1.0 to 5.0 times of molar weights and 1.0 to 2.0 times of molar weights, room temperature reaction was used CH after 10 hours under the argon atmospher 2Cl 2Extraction, drying, after concentrating, resistates is dissolved among the THF, ice-water bath cooling down, to wherein adding equivalent LiAlH4, room temperature reaction 3 hours adds the shrend reaction of going out, filtration is removed photoresist behind the body, the mother liquor ethyl acetate extraction, and after dry the concentrating, resistates obtains compound 12B with purification by silica gel column chromatography;
II. compound 12B is dissolved in DMSO and the acetic acid (3: 1), stir, heating, treat that raw material disappears after, reaction solution is poured in the frozen water into the saturated NaHCO of extracted with diethyl ether, organic phase 3The aqueous solution is washed, anhydrous sodium sulfate drying.Resistates obtains compound 12C with purification by silica gel column chromatography after filtering evaporate to dryness;
III. compound 12C is dissolved in CH 2Cl 2In, to the diisopropyl ethyl amine that wherein adds 1.0 to 2.0 times of molar weights, then slowly to the protection reagent that wherein splashes into 1.0 to 1.5 times of molar weights, the stirring at room reaction is spent the night, and adds water, behind the separatory, and water CH 2Cl 2Extraction merges organic phase, anhydrous sodium sulfate drying.After filtering evaporate to dryness, be dissolved among the THF, add the normal potassium hydroxide of 1.5-2.0, stirring at room is separated protection.Add water, ethyl acetate extraction, washing, drying.Filter evaporate to dryness, column chromatography obtains compound 12.
J. in an exsiccant round-bottomed flask, add the exsiccant methylene dichloride, under the Ar atmosphere, add oxalyl chloride, system is cooled to-78 ℃, slowly drip the dichloromethane solution that contains DMSO.Behind the 15min, the dichloromethane solution that will contain primary alconol 12 slowly adds system, reacts to add triethylamine after 1 hour.With system slowly rise to 0 ℃ continue to stir 15min after, add distilled water cancellation reaction, mixture uses extracted with diethyl ether, merges organic layer, uses the washing of saturated ammonium chloride (5mL * 2) and saturated aqueous common salt (5mL) successively, organic layer use anhydrous sodium sulfate drying.Filtering siccative, normal pressure steam and desolventize, and get crude product 12.In this reaction, oxalyl chloride, DMSO, the ratio of the molar weight of triethylamine is 1: 3: 6: 15.
K. take by weighing wittig salt 2 in an exsiccant round-bottomed flask, under the Ar atmosphere, add the exsiccant ether and stir 10min.System is reduced to 0 ℃ with ice-water bath, splash into the diethyl ether solution of MeLi rapidly, after system is risen to room temperature and stirs 30min, be cooled to 0 ℃ again, in system, splash into 3mL and contain the diethyl ether solution of aldehyde 13, dropwise the water-bath of recession deicing and rose to room temperature reaction 48 hours.Add distilled water cancellation reaction, mixture uses extracted with diethyl ether, merges organic layer, uses the washing of saturated ammonium chloride (5mL) and saturated aqueous common salt (5mL) successively, and organic layer uses anhydrous sodium sulfate drying.Filtering siccative, normal pressure steam and to desolventize, resistates use silica gel column chromatography separate faint yellow oily thing.
L. the olefin(e) compound 14 that previous step is obtained is dissolved in the Virahol, stirs to add ZrCl down 4System is heated to 50 ℃ and reacted 2 hours in oil bath, removes solvent under reduced pressure, add distilled water cancellation reaction, mixture uses ethyl acetate extraction, merges organic layer, uses the saturated common salt water washing, anhydrous sodium sulfate drying.The filtering siccative removes solvent under reduced pressure, and resistates uses silica gel column chromatography to separate, and gets faint yellow fluffy solid 1.
Below will discuss above-mentioned each step process of the present invention in detail:
Get Vitamin D2 (3,200g, 0.5mol) be dissolved in the pyridine (500mL), (200g is 1.05mol) with 4-dimethylamino pyridine (10g) to wherein adding Tosyl chloride in batches under stirring, stirring is spent the night, after treating that raw material disappears, stir down reaction solution is slowly poured in the saturated sodium bicarbonate aqueous solution (2000mL), stirred 30 minutes, extracted with diethyl ether, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates obtains compound 4 through purification by silica gel column chromatography.
1H?NMR(300MHz，δ，ppm)0.54(3H，s)，0.82(3H，d，J＝6.3Hz)，0.84(3H，d，J＝6.3Hz)，0.91(3H，d，J＝6.3Hz)，1.01(3H，d，J＝7.2Hz)，1.20-1.38(3H，m)，1.40-1.55(3H，m)，1.60-1.78(4H，m)，1.80-1.90(3H，m)，1.95-2.04(3H，m)，2.05-2.15(1H，m)，2.37-2.41(2H，m)，2.46(3H，s)，2.51(1H，dd，J＝3.6，13.8Hz)，2.75(1H，dd，J＝3.6，13.8Hz)，4.68(1H，m)，4.81(1H，s)，5.03(1H，s)，5.19(2H，m)，5.96(1H，d，J＝11.1Hz)，6.09(1H，d，J＝11.1Hz)，7.34(2H，d，J＝8.4Hz)，7.81(2H，d，J＝8.4Hz).
(280g 0.5mmol) adds methyl alcohol (2000ml) dissolving, stirs down to wherein adding NaHCO to get compound 4 3(1760g, 21mol), reflux 8h, behind the pressure reducing and steaming methyl alcohol, resistates is cooled to room temperature, adds ethyl acetate (2000ml) and stirs 20 minutes after-filtration, solid merges the spissated crude product in back with ethyl acetate (500ml) washing five times, filtrate, and silica gel column chromatography obtains compound 5.
1H?NMR(300MHz，δ，ppm)0.54(3H，s)，0.82(3H，d，J＝7.2Hz)，0.84(3H，d，J＝6.3Hz)，0.89(3H，d，J＝9.3Hz)，0.94(3H，d，J＝9.0Hz)，1.25-1.36(4H，m)，1.41-1.55(4H，m)，1.56-1.60(1H，m)，1.66-1.75(4H，m)，1.80-1.84(2H，m)，2.24(1H，m)，2.66(1H，m)，3.26(3H，s)，4.17(1H，d，J＝9.6Hz)，4.88(1H，s)，4.99(1H，d，J＝9.6Hz)，5.04(1H，s)，5.18-5.20(2H，m). 13C?NMR(75MHz，δ，ppm)12.2，14.0，17.6，18.1，19.4，19.9，20.1，21.1，22.0，22.6，23.6，27.6，28.3，33.0，33.4，36.3，40.1，40.2，42.8，45.3，55.0，56.4，72.5，104.2，118.4，132.0，135.4，144.2，154.6.
Get compound 5 (200g) and be dissolved in CH 2Cl 2-MeOH (1: 1,2000ml) in.Get SeO 2(30g) add CH 2Cl 2-MeOH (1: 1,500ml), (about 25%, 360ml), the stirring at room reaction is after 3 hours to the toluene solution that wherein adds the exsiccant peroxy tert-butyl alcohol again, the solution of second product 5 that goes on foot is slowly splashed into wherein (30min), after dripping off, continue stirring reaction 30min, to the aqueous solution (1000ml) that wherein slowly adds sodium bisulfite, add back stirring reaction 1h, CH 2Cl 2Extraction (1000ml) three times merges organic phase, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates obtains compound 6 by purification by silica gel column chromatography.Beginning to 6 three step of compound total recovery from vitamin D2 is 50%.
1H?NMR(300MHz，δ，ppm)0.54(3H，s)，0.81(3H，d，J＝7.2Hz)，0.83(3H，d，J＝6.3Hz)，0.90(3H，d，J＝7.2Hz)，1.01(3H，d，J＝6.3Hz)，1.21-1.33(4H，m)，1.42-1.52(4H，m)，1.60-1.75(4H，m)，1.81-1.85(2H，m)，1.95-2.02(4H，m)，2.24(1H，dd，J＝7.8，12.3Hz)，1.64(1H，d，J＝12.9Hz)，3.24(3H，s)，4.19(1H，d，J＝9.6Hz)，4.20(1H，m)，4.92(1H，d，J＝9.6Hz)，5.15-5.21(4H，m). 13C?NMR(75MHz，δ，ppm)12.2，14.1，17.6，18.1，19.6，19.9，20.1，21.1，22.1，22.6，23.6，27.7，29.3，33.0，33.7，36.3，40.2，40.3，42.8，45.3，55.9，56.4，72.5，104.9，118.4，132.0，135.4，144.2，154.6.EI-MS(m/z)[M +]426.3，394.3，353.2，269.1，219.0，135.0，68.9
(85g 0.2mol) is dissolved in exsiccant CH to get compound 6 2Cl 2(500ml), ice-water bath is cooled to 0 degree centigrade with it, to wherein add diisopropyl ethyl amine (40g, 0.31mol), then slowly to wherein splash into methoxymethyl chlorine (20g, 0.25mol), stirring at room reaction is spent the night, and adds water, behind the separatory, water CH 2Cl 2Extraction (300ml) three times merges organic phase, anhydrous sodium sulfate drying.After filtering evaporate to dryness, the resistates purification by silica gel column chromatography gets compound 7c.Yield 85%.
1H?NMR(300MHz，δ，ppm)0.54(3H，s)，0.81(3H，d，J＝6.0Hz)，0.85(3H，d，J＝8.4Hz)，0.91(3H，d，J＝7.2Hz)，1.01(3H，d，J＝6.3Hz)，1.25-1.36(4H，m)，1.41-1.50(5H，m)，1.70-1.81(4H，m)，1.81-1.83(1H，m)，1.92-2.01(4H，m)，2.21-2.50(1H，dd，J＝7.2，11.7Hz)，2.65(1H，d，J＝12.9Hz)，3.24(3H，s)，3.36(3H，s)，4.09(1H，d，J＝9.3Hz)，4.66-4.73(2H，m)，5.06-5.26(5H，m). 13C?NMR(75MHz，δ，ppm)12.2，14.1，17.6，17.8，19.6，19.9，20.8，22.1，22.5，24.0，27.7，29.4，29.7，32.3，33.1，33.4，40.3，42.8，45.3，55.2，55.4，55.9，56.5，76.8，105.8，119.5，132.0，135.5，143.7，151.3.ESI-HRMS(m/z)[M +]M+Na +493.3651(Calc.493.3652，error＝0.2pppm).
(4.7g 10.0mmol) is dissolved in CH to get the 4th step product 7c 2Cl 2-MeOH (1: 1,100ml) in, acetone-liquid nitrogen bath is cooled to-65 ℃, stirs down, feeds ozone 1h, then to wherein feeding the argon gas bubbling 5 minutes, adds NaBH in batches 4(2.2g), nature rises to room temperature under stirring, and adds saturated NH behind the 1h 4The cancellation of the Cl aqueous solution, CH 2Cl 2Extraction (50ml) three times merges organic phase, anhydrous sodium sulfate drying, and after the filtering and concentrating, resistates gets compound 8c with purification by silica gel column chromatography.Yield 56%.
1H?NMR(300MHz，δ，ppm)0.57(3H，s)，0.65(1H，m)，0.80-0.87(2H，m)，1.04(3H，d，J＝6.6Hz)，1.27-1.35(3H，m)，1.47-1.55(3H，m)，1.61-1.67(3H，m)，1.84-2.01(6H，m)，2.81(1H，d，J＝10.5Hz)，3.05(1H，s)，3.16(3H，s)，3.34(3H，s)，3.50(1H，m)，3.62(1H，dd，J＝2.1，10.5Hz)，3.65(1H，dd，J＝2.4，6.9Hz)，3.98(1H，d，J＝4.2Hz)，4.58(1H，d，J＝9.6Hz)，4.59(2H，m)，4.75(1H，d，J＝9.6Hz). 13C?NMR(75MHz，δ，ppm)9.6，11.8，16.8，18.2，22.2，23.6，27.1，29.3，31.0，34.3，39.0，40.3，45.5，52.8，55.5，55.6，67.7，72.6，73.9，77.2，96.2，119.3，144.0.ESI-HRMS(m/z)[M +]M+Na +＝431.2763(Calc.431.2768，error＝1.2ppm).
Compound 8a, compound 8b, synthetic equally as stated above.
8a： 1H?NMR(300MHz，δ，ppm)0.03(6H，s)，0.59(3H，s)，0.68(1H，m)，0.86(9H，s)，1.05(3H，d，J＝6.3Hz)，1.22-1.38(4H，m)，1.42-1.76(8H，m)，1.80-1.93(2H，m)，1.96-2.02(4H，m)，2.86(1H，b)，3.16(3H，s)，3.36(1H，dd，J＝6.9，10.5Hz)，3.64(1H，dd，J＝3.0，10.5Hz)，3.72(1H，d，J＝4.8Hz)，3.78-3.83(1H，m)，4.54(1H，d，J＝9.6Hz)，4.85(1H，d，J＝9.6Hz). 13C?NMR(75MHz，δ，ppm)-5.1，-4.7，9.0，11.7，16.9，18.0，19.1，22.2，23.7，25.7，27.2，29.5，33.9，35.1，40.4，45.6，52.9，55.6，55.7，67.9，72.2，73.0，120.2，143.4.ESI-HRMS(m/z)[M +]M+Na +＝501.3367(Cal?c.501.3371，error＝0.8ppm).
8b： 1H?NMR(300MHz，δ，ppm)0.34(1H，m)，0.56(3H，s)，0.63(1H，m)，1.05(3H，d，J＝6.3Hz)，1.25-1.37(5H，m)，1，44-1.60(6H，m)，1.67-1.74(3H，m)，1.97-2.17(4H，m)，2.05(3H，s)，2.69(1H，m)，3.20(3H，s)，3.39(1H，m)，3.64(1H，m)，3.79(1H，b)，4.26(1H，d，J＝4.2Hz)，4.61-4.72(2H，m). 13C?NMR(75MHz，δ，ppm)9.4，11.9，16.4，18.8，21.0，22.2，23.9，27.0，29.5，31.0，34.6，39.0，40.3，45.5，52.7，55.6，67.7，72.6，73.9，77.2，119.3，144.0，170.1.EI-MS(m/z)[M +]406.2，388.2，374.2，314.1，293.1，243.0，135.0..
Get the 5th step product 8c (41g) and be dissolved in CH 2Cl 2In, to wherein adding pyridine (12g), then, slowly to wherein splashing into diacetyl oxide (12g), stirred overnight at room temperature adds the shrend reaction of going out, two-phase separately after, water CH 2Cl 2Extraction (500ml) three times merges organic phase and washes with saturated common salt, anhydrous sodium sulfate drying, and after the filtering and concentrating, resistates obtains compound 9c with purification by silica gel column chromatography.Yield 90%.
1H?NMR(300MHz，δ，ppm)0.59(3H，s)，1.02(3H，d，J＝6.9Hz)，1.25-1.37(5H，m)，1.47-1.55(4H，m)，1.66-1.73(4H，m)，1.88-1.90(1H，m)，1.94-1.98(2H，m)，2.04(3H，s)，2.83(1H，dd，J＝3.3，9.9Hz)，2.99(1H，s)，3.18(3H，s)，3.35(3H，s)，3.70(1H，m)，3.79(1H，dd，J＝7.5，11.1Hz)，3.98(1H，d，J＝2.7Hz)，4.08(1H，dd，J＝3.6，10.2Hz)，4.59-4.64(2H，m)，4.78(1H，d，J＝9.3Hz). 13CNMR(75MHz，δ，ppm)9.6，11.9，17.3，18.3，21.0，22.2，23.6，29.4，31.1，34.4，36.1，40.3，45.6，53.2，55.5，69.4，72.6，73.8，77.2，96.3，119.6，126.0，143.8，171.3，181.6.
(45g 100mmol) is dissolved in DMSO (300ml) and the acetic acid (100ml), stirs to get the 6th step product 9c, be heated to 70 ℃, treat that raw material disappears after, reaction solution is poured in the frozen water, extracted with diethyl ether, organic phase is washed anhydrous sodium sulfate drying with the saturated NaHCO3 aqueous solution.Resistates obtains compound 10 with purification by silica gel column chromatography after filtering evaporate to dryness.Yield 70%.
1H?NMR(300MHz，δ，ppm)0.87(3H，s)，1.02(3H，d，J＝6.6Hz)，1.19-1.30(3H，m)，1.39-1.48(3H，m)，1.72-1.96(6H，m)，1.96(3H，s)，1.95-2.08(3H，m)，2.11(1H，m)，2.37(1H，m)，3.33(3H，s)，3.32(1H，m)，3.74(1H，m)，3.82(1H，m)，4.06(1H，m)，4.11(1H，m)，4.57(2H，m)，5.88(1H，d，J＝16.2Hz)，6.30(1H，d，J＝15.9Hz). 13C?NMR(75MHz，δ，ppm)16.0，17.4，18.1，18.8，20.9，24.6，25.6，26.6，31.0，33.3，34.6，37.0，43.6，53.1，55.6，69.3，72.6，96.1，124.1，126.3，127.7，146.7，171.3.ESI-HRMS(m/z)[M +]M+Na +573.3585(Calc.573.3582，error＝0.5ppm)，533.3654，473.3457.
Get above-mentioned the 7th step product 10c (4.5g) and be dissolved among the DMF (150mL), add imidazoles (15 gram) and TBDMSCl (16.5 restrain), stirring at room is reacted to raw material and is disappeared.Reaction solution is poured in the water, and extracted with diethyl ether merges organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates obtains flower compound 11c with purification by silica gel column chromatography.Yield 75%.
In an exsiccant 50mL round-bottomed flask; add 10mL exsiccant methylene dichloride; under the Ar atmosphere; getting above-mentioned the 8th step product 11c (5.0g) is dissolved among the exsiccant CH2Cl2 (50mL); cryosel is bathed and is cooled to-10 ℃; stir down; to wherein adding triethylamine (3.1g),, drip off the back and continue stirring reaction 3h then slowly to wherein splashing into methylsulfonyl chloride (1.6g); pressure reducing and steaming solvent under the normal temperature; resistates is dissolved among the exsiccant THF, and under the argon shield, cryosel is bathed and is cooled to-10 ℃; in batches to wherein adding LiAlH4; add the back and continue to stir 3 hours, to wherein slowly splashing into ethyl acetate (2mL), and then slowly splash into water (10mL); ethyl acetate extraction (50mL) three times; merge organic phase and wash with saturated common salt, anhydrous sodium sulfate drying is behind the filtration evaporate to dryness; resistates obtains compound 12c with purification by silica gel column chromatography, yield 22%.
Add 0.27mL oxalyl chloride (3mmol), system is cooled to-78 ℃, slowly drip the dichloromethane solution 5mL that contains 468mg (6mmol) DMSO.Behind the 15min, the dichloromethane solution 10mL that will contain 492mg (1mmol) primary alconol 12c slowly adds system, reacts to add 2.3mL (15mmol) triethylamine after 1 hour.With system slowly rise to 0 ℃ continue to stir 15min after, add 5mL distilled water cancellation reaction, mixture uses the extracted with diethyl ether of 100mL * 3, merges organic layer, use the washing of saturated ammonium chloride (5mL * 2) and saturated aqueous common salt (5mL) successively, organic layer uses anhydrous sodium sulfate drying.Filtering siccative, normal pressure steam and to desolventize, resistates with the toluene dissolving after evaporated under reduced pressure again, behind the triplicate resistates is drained on oil pump, crude product 490mg, productive rate 99%, crude product need not to separate and can be directly used in next step reaction.(product R f≈ 0.8, PE: EtOAc=16: 1), and the 13c. of silica gel column chromatography
1H?NMR(300MHz，δ，ppm)0.05(6H，s)，0.57(3H，s)，0.86(9H，s)，1.12(3H，d，J＝6.9Hz)，1.40(1H，m)，1.50-1.75(8H，m)，1.87-2.02(4H，m)，2.06-2.16(1H，m)，2.29-2.43(3H，m)，2.54(1H，dd，J＝6.0，14.1Hz)，2.82(1H，dd，J＝3.9，10.5Hz)，3.34(3H，s)，3.95-4.03(2H，m)，4.64(2H，dd，J＝6.6，9.3Hz)，5.84(1H，d，J＝11.1Hz)，6.20(1H，d，J＝11.7Hz)，9.57(1H，s). 13C?NMR(75MHz，δ，ppm)-4.7，12.4，13.5，18.1，22.6，23.1，25.8，26.4，28.6，33.5，40.1，40.7，45.8，46.0，49.7，51.3，55.2，55.4，67.8，72.7，94.8，116.2，121.8，133.5，140.5，205.0.ESI-HRMS(m/z)[M+K +]529.3118，[M+Na +]513.3370(Calc.513.3371，error＝0.2ppm)，[M+NH 4 +]508.3826.
Compound 13a, 13b such as above-mentioned method are synthetic:
Figure B2009101364413D0000161
a： 1H?NMR(300MHz，δ，ppm)1.13(3H，d，J＝6.9Hz)，1.43(1H，m)，1.50-1.79(8H，m)，1.89-2.00(4H，m)，2.09-2.26(1H，m)，2.29-2.43(3H，m)，2.59(1H，dd，J＝6.0，14.1Hz)，2.87(1H，dd，J＝3.9，10.5Hz)，4.35-4.58(2H，m)，5.89(1H，d，J＝11.1Hz)，6.26(1H，d，J＝11.7Hz)，7.55(4H，m)，7.65(2H，m)，8.03(4H，m)，9.59(1H，s). 13C?NMR(75MHz，δ，ppm)18.0，22.8，23.4，26.0，26.9，28.7，33.6，40.1，40.7，45.8，46.0，49.7，55.2，55.0，67.2，72.4，116.5，122.8，128.6，129.5，129.9，133.1，133.3，135.5，140.5，165.9，165.7，204.1.ESI-HRMS(m/z)[M+H +]541.2950(Calc.541.2954，error＝0.8ppm).
13b： 1H?NMR(300MHz，δ，ppm)0.03(6H，s)，0.53(6H，s)，0.86(18H，s)，1.10(3H，d，J＝6.9Hz)，1.41(1H，m)，1.50-1.70(8H，m)，1.80-2.01(4H，m)，2.01-2.12(1H，m)，2.25-2.40(3H，m)，2.52(1H，dd，J＝6.0，14.1Hz)，2.80(1H，dd，J＝3.9，10.5Hz)，3.85-4.00(2H，m)，5.82(1H，d，J＝11.1Hz)，6.17(1H，d，J＝11.7Hz)，9.51(1H，s). 13C?NMR(75MHz，δ，ppm)-4.7，-4.5，12.2，12.6，13.6，18.0，22.3，23.1，25.2，25.8，26.4，28.6，33.0，40.3，40.6，45.8，46.0，49.7，55.0，55.3，67.3，72.4，116.2，121.8，133.3，140.9，204.5.ESI-HRMS(m/z)[M+H +]561.4157(Calc.561.4159，error＝0.4ppm).
12-1's is synthetic:
In an exsiccant 50mL round-bottomed flask, add 10mL exsiccant methylene dichloride, under the Ar atmosphere, get compound 9 (R1=tertiary butyl dimethyl is silica-based, the R2=benzoyl) and (5.0g) be dissolved in exsiccant CH 2Cl 2(50mL); cryosel is bathed and is cooled to-10 ℃; stir down; to wherein adding triethylamine (3.1g); then slowly to wherein splashing into methylsulfonyl chloride (1.6g); drip off the back and continue stirring reaction 3h, pressure reducing and steaming solvent under the normal temperature, resistates are dissolved among the exsiccant THF; under the argon shield; cryosel is bathed and is cooled to-10 ℃, in batches to wherein adding 1.2 equivalent LiAlH4, adds the back and continues to stir 3 hours; to wherein slowly splashing into ethyl acetate (2mL); and then slowly splashing into water (10mL), ethyl acetate extraction (50mL) three times merges organic phase and washes with saturated common salt; anhydrous sodium sulfate drying; after filtering evaporate to dryness, resistates obtains compound 12-1 with purification by silica gel column chromatography, yield 42%.
12-2's is synthetic:
Get product 12-1 (5g) and be dissolved in DMSO (30ml) and the acetic acid (10ml), stir, be heated to 50 ℃, treat that raw material disappears after, reaction solution is poured in the frozen water into the saturated NaHCO of extracted with diethyl ether, organic phase 3The aqueous solution is washed, anhydrous sodium sulfate drying.Resistates obtains compound 12-2 with purification by silica gel column chromatography after filtering evaporate to dryness.Yield 80%.
12 synthetic (R1=tertiary butyl dimethyl is silica-based, R2=benzoyl, R3=tertiary butyl dimethyl is silica-based):
Get product 12-2 (4.5g) and be dissolved among the DMF (150mL), add imidazoles (15 gram) and TBDMSCl (16.5 restrain), stirring at room is reacted to raw material and is disappeared.Reaction solution is poured in the water, and extracted with diethyl ether merges organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.After filtering evaporate to dryness, resistates is dissolved in THF50ml, and argon shield adds 2 normal KOH down, and stirring at room to raw material disappears.Add entry and ethyl acetate in the reaction system, branch vibration layer, the solvent layer washing, the organic layer drying is filtered, and concentrates.The resistates silica gel column chromatography obtains compound 12b, yield 65%.
Reactions steps K:
Take by weighing 534mg (1mmol) wittig salt in an exsiccant 25mL round-bottomed flask, under the Ar atmosphere, add 10mL exsiccant ether and stir 10min.System is reduced to 0 ℃ with ice-water bath, and (this moment, system formed brown mixture (solid obviously reduces) for 1.6M, the 0.96mmol) diethyl ether solution of MeLi to splash into 0.6mL rapidly.After system risen to room temperature and stir 30min, again be cooled to 0 ℃, in system, splash into 3mL and contain the diethyl ether solution of 123mg (0.25mmol) aldehyde, mixture brown taken off (rise to room temperature and a large amount of white solids can occur after about 1 hour) rapidly in this moment system, dropwises the water-bath of recession deicing and rises to room temperature reaction 48 hours.Add 5mL distilled water cancellation reaction, mixture uses the extracted with diethyl ether of 100mL * 3, merges organic layer, uses the washing of saturated ammonium chloride (5mL) and saturated aqueous common salt (5mL) successively, and organic layer uses anhydrous sodium sulfate drying.Filtering siccative, normal pressure steam and desolventize, and resistates uses silica gel column chromatography to separate (PE: EtOAc=16: 1), get the faint yellow oily thing of 50mg, productive rate 32%.
1H?NMR(300MHz，δ，ppm)0.05(6H，s)，0.51(3H，s)，0.87(9H，s)，0.97(6H，d，J＝6.3Hz)，1.13(1H，m)，1.16(3H，s)，1.21(3H，s)，1.32-1.39(3H，m)，1.44-1.73(8H，m)，1.94-1.99(3H，m)，2.13(1H，dd，J＝4.5，12.9Hz)，2.29(1H，m)，2.41(1H，m)，2.56(1H，dd，J＝5.4，12.9Hz)，2.78(1H，m)，3.36(3H，s)，3.37(3H，s)，4.02(2H，m)，4.64(2H，dd，J＝6.9，11.1Hz)，4.72(2H，dd，J＝6.9，12.3Hz)，5.19(2H，m)，5.81(1H，d，J＝11.1Hz)，6.21(1H，d，J＝10.8Hz).
Reactions steps L:
The olefin(e) compound 50mg (0.08mmol) that previous step is obtained is dissolved in the 2mL Virahol, stirs to add 50mg (0.2mmol) ZrCl down 4System is heated to 50 ℃ and reacted 2 hours in oil bath, removes solvent under reduced pressure, add 5mL distilled water cancellation reaction, mixture uses the ethyl acetate extraction of 100mL * 3, merge organic layer, use saturated aqueous common salt (5mL) washing, organic layer uses anhydrous sodium sulfate drying.The filtering siccative removes solvent under reduced pressure, and resistates uses silica gel column chromatography to separate (EtOAc), gets the faint yellow oily thing of 18mg (can form faint yellow fluffy solid after draining on the oil pump), productive rate 55%.
1H?NMR(300MHz，δ，ppm)0.58(3H，s)，0.99(6H，m)，1.18(3H，s)，1.26(3H，s)，1.38(1H，m)，1.46(3H，m)，1.67-1.83(8H，m)，1.92-2.00(3H，m)，2.19-2.27(2H，m)，2.48(1H，m)，2.71(1H，m)，2，79(1H，m)，4.05(1H，m)，4.11(1H，m)，5.18(1H，dd，J＝9.9，11.1Hz)，5.35(1H，dd，J＝9.6，11.1Hz)，5.84(1H，d，J＝11.1Hz)，6.30(1H，d，J＝11.1Hz). 13C?NMR(75MHz，δ，ppm)12.4，16.4，21.7，21.3，22.2，25.4，26.6，26.9，27.7，28.9，34.0，37.0，40.3，42.1，42.7，44.6，45.6，56.2，60.4，67.1，72.7，115.3，123.2，128.2，131.3，138.3，142.7.ESI-HRMS(m/z)[M+NH 4 +]434.3623(Cal?c.434.3629，error＝1.4ppm).
By above-mentioned synthesis step L, can synthetic compound 14 as follows:
1H?NMR(300MHz，δ，ppm)0.05(6H，s)，0.51(3H，s)，0.87(9H，s)，0.97(6H，d，J＝6.3Hz)，1.13(1H，m)，1.16(3H，s)，1.21(3H，s)，1.32-1.39(3H，m)，1.44-1.73(8H，m)，1.94-1.99(3H，m)，2.13(1H，dd，J＝4.5，12.9Hz)，2.29(1H，m)，2.41(1H，m)，2.56(1H，dd，J＝5.4，12.9Hz)，2.78(1H，m)，3.36(3H，s)，3.37(3H，s)，4.02(2H，m)，4.64(2H，dd，J＝6.9，11.1Hz)，4.72(2H，dd，J＝6.9，12.3Hz)，5.19(2H，m)，5.81(1H，d，J＝11.1Hz)，6.21(1H，d，J＝10.8Hz).
13C?NMR(75MHz，δ，ppm)-5.0，13.1，18.4，20.2，20.9，24.2，24.6，25.1，24.9，25.8，26.0，27.1，27.8，32.1，37.3，38.0，40.3，42.0，46.0，47.9，55.1，55.6，56.3，57.2，67.5，78.2，93.0，48.6，73.2，122.3，131.2，134.9，144.0，149.1.ESI-HRMS(m/z)[M +]M+Na +618.4176(Cacl.618.4180，error＝0.6ppm)
Figure B2009101364413D0000191
1H?NMR(300MHz，δ，ppm)0.05(6H，s)，0.07(6H，m)，0.09(6H，s)，0.51(3H，s)，0.87(9H，s)，0.90(9H，s)，0.97(6H，d，J＝6.3Hz)，1.01(9H，m)，1.13(1H，m)，1.16(3H，s)，1.21(3H，s)，1.32-1.39(3H，m)，1.44-1.73(8H，m)，1.94-1.99(3H，m)，2.13(1H，dd，J＝4.5，12.9Hz)，2.29(1H，m)，2.41(1H，m)，2.56(1H，dd，J＝5.4，12.9Hz)，2.78(1H，m)，4.02(2H，m)，5.19(2H，m)，5.81(1H，d，J＝11.1Hz)，6.21(1H，d，J＝10.8Hz).
13C?NMR(75MHz，δ，ppm)-5.0，-4.1，-2.2，13.1，13.5，15.6，18.4，20.2，20.9，24.2，24.6，25.1，26.0，27.1，27.8，32.1，37.3，38.0，40.3，42.0，46.0，47.9，55.1，55.6，67.5，78.2，93.0，48.6，73.2，122.3，131.2，134.9，144.0，149.1.ESI-HRMS(m/z)[M +]M+Na +742.5924(Cacl.742.5934，error＝1.4ppm)
Figure B2009101364413D0000192
The above, it only is preferred embodiment of the present invention, be not that the present invention is done any pro forma restriction, though the present invention discloses as above with preferred embodiment, yet be not in order to limit the present invention, any those skilled in the art, in not breaking away from the technical solution of the present invention scope, when the technology contents that can utilize above-mentioned announcement is made a little change or is modified to the equivalent embodiment of equivalent variations, in every case be not break away from the technical solution of the present invention content, according to technical spirit of the present invention to any simple modification that above embodiment did, equivalent variations and modification all still belong in the scope of technical solution of the present invention.

Claims (10)

1. the preparation method of a Zemplar is characterized in that, said method comprising the steps of:
A) at first the hydroxyl of vitamin D2 is obtained compound 4 with sulphonate protection, under the effect of alkali, in methyl alcohol, compound 4 intramolecular cyclizations obtain compound 5, again compound 5 are carried out allylic oxidation, obtain compound 6 then;
B) hydroxyl of compound 6 protected after, obtain compound 7, by optionally cutting off the outer terminal double link of ring in the compound 7 and two keys of side chain, and by obtaining diol compound 8 with the cancellation reaction, and then optionally protect the one-level hydroxyl in the compound 8 to obtain compound 9 with acyl group, the triatomic ring of opening under acidic conditions in 9 obtains glycol 10;
C) utilize the sterically hindered difference of two hydroxyls in the compound 10 optionally to protect a hydroxyl to obtain compound 11 with silicon ether, and then with the another one hydroxyl in the sulphonate protection 11, and reduce with LiAlH4 and to slough sulphonate and ethanoyl obtains compound 12;
D) after compound 12 obtains compound 13 by the Swern oxidation, with side chain 2 the Wittig reaction taking place and obtain compound 14, slough three protecting groups in the compound 14 at last, obtains the target compound Zemplar.
2. the preparation method of Zemplar according to claim 1, it is characterized in that: in the step b), the hydroxyl of described compound 6 can be protected with R1, obtains compound 7,
Figure F2009101364413C0000011
R1 can be an ethanoyl, benzoyl, tertiary butyl dimethyl-silicon, triethyl silicon or methoxyl methyl.
3. the preparation method of Zemplar according to claim 1 is characterized in that: outer terminal double link of the ring in the described selective rhizotomy compound 7 and pendant double bonds can be undertaken by ozonization.
4. the preparation method of Zemplar according to claim 1 is characterized in that: the primary hydroxyl in the described compound 8 obtains compound 9 with the R2 protection,
Figure F2009101364413C0000021
R2 can be the acetyl or benzoyl base.
5. the preparation method of Zemplar according to claim 1, it is characterized in that: in the step c), a hydroxyl of 3 in the selective protection compound 10 is to obtain compound 11 with protecting group R3,
Figure F2009101364413C0000022
R3 can be trimethyl silicon based, and triethyl is silica-based, and tertiary butyl dimethyl is silica-based, triisopropylsilyl, the silica-based or benzoyl of tert-butyl diphenyl.
6. the preparation method of Zemplar according to claim 1; it is characterized in that: the used sulphonate of hydroxyl in the protection compound 11 can be: methanesulfonates, p-toluenesulfonic esters, benzene sulfonate; closilate is to fluorobenzene sulphonate or triflate.
7. the preparation method of Zemplar according to claim 1, it is characterized in that: the used reagent of sloughing in the compound 14 of protecting group can be protonic acid or Lewis acid.
8. the preparation method of Zemplar according to claim 7, it is characterized in that: described protonic acid can be a hydrochloric acid, sulfuric acid, tosic acid, camphorsulfonic acid or tosic acid pyridinium salt; Described Lewis acid can be BF 3, ZnI 2, ZrCl 4Or MgBr 2
9. the preparation method of Zemplar according to claim 1, it is characterized in that: in the step d), the structural formula of described side chain 2 and compound 14 is as follows:
Figure F2009101364413C0000023
Side chain 2
Figure F2009101364413C0000031
The protecting group R4 of described side chain 2 and compound 14 can be a methoxymethyl, hydrogen, and triethyl is silica-based or trimethyl silicon based.
10. according to the preparation method of claim 5 or 6 described Zemplars, it is characterized in that: compound 11 can also obtain by following reaction formula from compound 9:
Figure F2009101364413C0000032
Wherein, R1 can be an ethanoyl, benzoyl, tertiary butyl dimethyl-silicon, triethyl silicon or methoxy first; R2 can be the acetyl or benzoyl base; R3 can be trimethyl silicon based, and triethyl is silica-based, and tertiary butyl dimethyl is silica-based, triisopropylsilyl, the silica-based or benzoyl of tert-butyl diphenyl.
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CN103086937A (en) * 2013-01-08 2013-05-08 上海朴颐化学科技有限公司 Method for synthesizing paricalcitol
CN103965087A (en) * 2014-05-05 2014-08-06 湖南华腾制药有限公司 Synthesis process for key intermediate of paricalcitol
CN107286067A (en) * 2016-04-05 2017-10-24 湖南华腾制药有限公司 A kind of preparation method of Maxacalcitol
CN114773151A (en) * 2021-12-30 2022-07-22 正大制药（青岛）有限公司 Preparation method of paricalcitol 20S isomer impurity
CN114805157A (en) * 2022-04-22 2022-07-29 正大制药（青岛）有限公司 Stable paricalcitol and preparation method thereof

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US7491712B1 (en) * 2007-12-10 2009-02-17 Formosa Laboratories, Inc. Process for preparation of paricalcitol and intermediates thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013023327A1 (en) * 2011-08-15 2013-02-21 上海皓元化学科技有限公司 Side chain of 25-hydroxyvitamin d2 series drug and preparation method thereof
CN103086937A (en) * 2013-01-08 2013-05-08 上海朴颐化学科技有限公司 Method for synthesizing paricalcitol
CN103965087A (en) * 2014-05-05 2014-08-06 湖南华腾制药有限公司 Synthesis process for key intermediate of paricalcitol
CN107286067A (en) * 2016-04-05 2017-10-24 湖南华腾制药有限公司 A kind of preparation method of Maxacalcitol
CN114773151A (en) * 2021-12-30 2022-07-22 正大制药（青岛）有限公司 Preparation method of paricalcitol 20S isomer impurity
CN114805157A (en) * 2022-04-22 2022-07-29 正大制药（青岛）有限公司 Stable paricalcitol and preparation method thereof

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