CN107501317A - A kind of preparation method of paricalcitol intermediate - Google Patents

A kind of preparation method of paricalcitol intermediate Download PDF

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CN107501317A
CN107501317A CN201710823374.7A CN201710823374A CN107501317A CN 107501317 A CN107501317 A CN 107501317A CN 201710823374 A CN201710823374 A CN 201710823374A CN 107501317 A CN107501317 A CN 107501317A
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compound
preparation
organic solvent
paricalcitol
mol ratio
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CN107501317B (en
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李洪坤
丁福斗
孙敏
张宪恕
高强
郑保富
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Shanghai Hao Yuan Pharmaceutical Ltd By Share Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a kind of preparation method of paricalcitol intermediate, comprise the steps of：1) after shikimic acid is esterified, 2) 3,5 hydroxyls of selective protection；3) 4 hydroxyls are used and N, N' thiocarbonyl group are protected；4) thiocarbonyl ester is removed；5) by double bond epoxidation；6) reduce；7) aoxidize, finally give a kind of paricalcitol intermediate.Raw material selection of the present invention is cheap and easy to get, and all chiral centres introduce by raw material, and reaction is not related to any chiral centre, and product quality is easy to control, is advantageous to industrialized production.

Description

A kind of preparation method of paricalcitol intermediate
Technical field
The present invention relates to a kind of preparation method of paricalcitol intermediate.
Background technology
Vitamin D (vitamin D) is sterol analog derivative, has anti-rachitic effect, also known as antirachitic vitamin.Mesh Before think that vitamin D is also a kind of steroid hormone, most important member is VD2 (calciferols in vitamin D family member Alcohol) and VD3 (Vitamin D3).Vitamin D is derivative of the different provitamin Ds after ultraviolet irradiation.American scientist One research of 40 years by a definite date finds that taking one vitamin D daily can be the risk for suffering from breast cancer, colon cancer and oophoroma Reduce half.For sunlight on skin, body will produce vitamin D, and this some vitamin D accounts for the supply of body vitamin D 90%.
In recent years, increasing evidence showed, the D that is deficient in vitamin may be extremely harmful to body.It is thought that heart The diseases such as disease, tuberculosis, cancer, diabetes, hypertension, schizophrenia and multiple sclerosis form all close with the D that is deficient in vitamin Cut is closed.
Paricalcitol (Paricalcitol, chemical name：19- removes first (nor) -1 α, 3 β, 25- trihydroxies -9,10- Secoergosta-5 (Z), 7 (Z), 22 (E)-triolefins；Synonym 19- removes first -1 α, 25- dihydroxyvitamin D 2) tieed up for activity Raw plain D medicines, available for prevention and treatment secondary hyperparathyroidism (SHPT), to receiving to dialyse and transplanting The SHPT of preoperative III and IV phases chronic renal disease (CKD) patient shows prevention and treatment curative effect, it has also become dialysis is suffered from The most widely used SHPT preventions of person and medicine, parathyroid hormone (PTH) is reduced by convenient oral administration Level, while there is minimum influence to blood calcium and serum phosphorus levels, and PTH reductions are a key fingers of SHPT treatment curative effects Mark.The structural formula of paricalcitol is shown in formula 1：
Synthesis paricalcitol mainly has following two methods in the prior art：
Method 1 is reported by WO2008053961, JP053392300, using steroidal compounds lumisterol as initiation material, synthesis Reaction is more than 17 steps.Wherein, the Julia coupling alkylene yields used when connecting side chain are low, use Na-Hg very not environmentally； Several steps reaction when being converted to exocyclic double bond, selectivity is bad, as dihydroxylation may oxidized side chain it is double Key, the route are not suitable for industrialized a large amount of productions.
Method 2 is reported by US5281731, US5086191, is employed the strategy of convergence, is first respectively synthesized two fragments, Then the compound of vitamin D structure is obtained in flakes again, deprotection obtains paricalcitol, and the route is as a result of remittance Poly- method, reduce synthesis risk, be advantageous to the quality control of final products, thus paricalcitol it is a large amount of it is industrially prepared on There is larger advantage compared with method 1.But the defects of route is there is also in terms of cost, hexatomic ring fragment compound X is from natural Chinic acid, though the compound can be obtained by natural product extraction, expensive due to yielding poorly, about 1.3 ten thousand RMB are every Kilogram, the initial cost for thus preparing compound II is very high.
In summary, there is restriction in the key intermediate X for the paricalcitol reported at present synthetic route The factor of industrial amplification production.Therefore, to realize that a large amount of productions of paricalcitol have to one safe and feasible of searching Synthetic route.
The content of the invention
The technical problem to be solved in the present invention is：There is provided a kind of safety cheap paricalcitol key intermediate preparation side Method.
In order to solve the above technical problems, the present invention adopts the technical scheme that：
A kind of preparation method of paricalcitol intermediate, is comprised the steps of：
1) shikimic acid is in the presence of chloroacetic chloride, and alkylol R1OH reacts, and shikimate IV is made,
2) compound IV in organic solvent, under phase transfer catalyst and catalyst action, under alkalescence condition, and chlorosilane Reagent R2Cl reacts, and compound V is made,
3) in organic solvent, under condensing agent effect, with N, chemical combination is made in the reaction of N'- thiocarbonyldiimidazoles to compound V Thing VI,
4) compound VI removes thiocarbonyl ester and obtains compound VII,
5) compound VII in organic solvent, under pro-oxidant effect, reacts with vanadyl acetylacetonate, compound is made VIII,
6) compound VIII in organic solvent, under reducing agent effect, is reduced obtained compound IX,
7) compound IX is dissolved in organic solvent, adds the aqueous solution of sodium metaperiodate, reacted and compound X is made,
Wherein R1For methyl either ethyl or isopropyl, R2For silicon ethers protection group, it is preferred that R2 be selected from TES, TBDMS, TBDPS, DIPS, DPS or TIPDS, most preferably, R2 TBDMS.
In step 1, the alkylol R1One or more of the OH in methanol, ethanol or isopropanol, preferably methanol； The shikimic acid is in alkylol R1Concentration in OH is 0.1~0.02g/mL, the mol ratio 1 of the shikimic acid and chloroacetic chloride:1~ 1:1.2.The alkylol is used as reactant and reaction dissolvent simultaneously.
In step 2, the organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, DMF, dioxane, ethyl acetate, One or more in toluene, preferably DMF；The alkali is selected from triethylamine, the one or more in tri-n-butylamine or DBU, Preferably triethylamine；The phase transfer catalyst is selected from tetramethyl amine bromide, four butyl bromation amine or benzyl triethyl ammonium bromination Amine, preferably four butyl bromation amine；The catalyst is DMAP, the chlorosilane reagent R2Cl be selected from TESCl, TBDMSCl, TBDPSCl, DIPSCl, DPSCl or TIPDSCl, preferably tert-butyl chloro-silicane.
In step 2, the compound IV and alkali, phase transfer catalyst, catalyst, the mol ratio of chlorosilane reagent are 1: 0.1:0.1:3 to 1:0.3:0.3:5；The concentration of the compound IV in organic solvent is 0.5~1.4mol/L.
In step 3, the organic solvent is selected from dichloromethane, chloroform or acetonitrile, preferably dichloromethane；The condensation Agent is selected from DMAP or pyridine, preferably DMAP.
In step 3, the compound V, the mol ratio of DMAP and N, N'- thiocarbonyldiimidazole is 1:0.1: 1.2 to 1:0.5:3；The concentration of the compound V in organic solvent is 0.2~0.5mol/L, preferably 0.2~0.24mol/ L。
In step 4, the removing comprises the following steps：Compound VI and potassium dihydrogen phosphate are dissolved in organic solvent, added Under heat to counterflow condition, the solution of AIBN and triethylamine in the organic solvent is added dropwise, reacts complete to compound VI reactions； The organic solvent is selected from glycol monoethyl ether or glycol dimethyl ether, or the mixing of two kinds of solvents；The compound VI, phosphorus The mol ratio of acid dihydride potassium, AIBN and triethylamine is 1:3:0.1:1 to 1:7:0.3:1.5, preferably 1:3:0.1:1~1:5: 0.2:1；The concentration of compound VI in organic solvent is 0.07mol/L.
In step 5, the pro-oxidant is tertbutanol peroxide or hydrogen peroxide, preferably tertbutanol peroxide；It is described Organic solvent is dichloromethane or chloroform；Compound VII, the mol ratio for stating pro-oxidant and vanadyl acetylacetonate are 1:2: 0.03 to 1:3:The concentration of 0.05, compound VII in the organic solvent is 0.2~0.25mol/L.
In step 6, the reducing agent used that reduces is lithium aluminium hydride reduction, and the organic solvent is selected from ether, tetrahydrofuran Or the one or more in methyl tertiary butyl ether(MTBE), the mol ratio of the compound VIII and reducing agent are 1:4 to 1:8, compound Concentration of the VII in the organic solvent is 0.1~0.2mol/L.
In step 7, the organic solvent is THF or dioxane, the mol ratio of the compound IX and sodium metaperiodate For 1:3 to 1:The concentration of 6, the compound IX in the organic solvent is 0.1~0.2mol/L.
Compound X in organic solvent, under alkalescence condition, reacts with trimethyl silicane ethyl, compound can be made XI, compound XI react with DIBAL-H in organic solvent, and compound II can be made, prepare specific method and refer to patent Method disclosed in US5281731.
Beneficial effect：
1) initiation material selection of the present invention is shikimic acid cheap and easy to get, and the price of Industrial raw material is about 750 yuan of people Every kilogram of coin, it is the 5~7% of prior art initiation material chinic acid, route cost is greatly reduced；
2) compound VII prepare compounds VIII reagent is tertbutanol peroxide cheap and easy to get, and cost is cheap；
3) all chiral centres in variation route introduce by raw material, and reaction is not related to any chiral centre, for chemical combination Thing X quality is easily controlled.
Embodiment
According to following embodiments, the present invention may be better understood.It is however, as it will be easily appreciated by one skilled in the art that real Apply the content described by example and be merely to illustrate the present invention, without should be also without limitation on sheet described in detail in claims Invention.
In the present invention, Me represents methyl；Et represents ethyl；I-Pr represents isopropyl；AIBN represents azo-bis-isobutyl cyanide； TCDI represents 1,1 '-thio-carbonyldiimidazole；DMAP represents DMAP；DIBAL-H represents diisobutyl aluminium hydride； THF represents tetrahydrofuran；DMF represents N,N-dimethylformamide；DBU represents 1,8- diazabicylos [5.4.0] 11 carbon -7- Alkene；TBDMSCl represents tert-butyl chloro-silicane；TLC represents thin-layer chromatography；
Embodiment 1：Compound IV preparation
Shikimic acid (50g, 0.287mol) is dissolved in the methanol of 500mL dryings, is cooled to 0 DEG C under nitrogen protection, adds Enter chloroacetic chloride (23.4g, 0.3mol) and warm naturally to room temperature, keeping temperature is reacted to TLC detection raw material spots and disappeared, reacted Finish.Reaction is quenched with water, ethyl acetate extraction, merges organic phase, saturated common salt washing, anhydrous Na2SO4Dry, be concentrated to give shallow The crude product of yellow oil.Crude product obtains the compound IV 51g of 54g light yellow oils using silica gel column chromatography, and yield is 95%.
1HNMR(400MHz,CDCl3) 6.75 (s, 1H), 4.40 (d, 1H, J=12.1Hz), 4.05 (d, 1H, J= 3.1Hz), 3.83 (m, 1H), 3.75 (s, 3H), 2.49 (dd, 1H, J=14.1Hz), 2.26 (d, 2H, J=6.1Hz), LC-MS (ESI-TOF):alcd for[C8H12O5]+188.07,found 188.07.
Embodiment 2：Compound V preparation
Compound IV (50g, 0.266mol) is dissolved in 200mL dry DMFs, adds (5.0g, 26.6mmol) tetrabutyl bromine Change ammonium, DMAP (5.0g, 40.9mmol) and TBDMSCl (159.6g, 1.064mol), be cooled under nitrogen protection zero degree with Under, triethylamine (200g, 2.0mol) is added, room temperature is warmed naturally to after finishing, reacts to TLC detection raw material spots and disappears, instead It should finish.Add saturated aqueous ammonium chloride reaction is quenched, ethyl acetate extraction, merge organic phase, saturated common salt washing, nothing Water Na2SO4Dry, concentrate the crude product of give light yellow oil.Crude product obtains 105.1g light yellow oils using silica gel column chromatography Compound V, yield 95%.
1HNMR(400MHz,CDCl3):6.75 (s, 1H), 4.40 (d, 1H, J=12.1Hz), 4.05 (d, 1H, J= 3.1Hz), 3.83 (m, 1H), 3.75 (s, 3H), 2.49 (dd, 1H, J=14.1Hz), 2.26 (d, 2H, J=6.1Hz), 0.885 (s,9H),0.855(s,9H),0.125(s,3H),0.114(s,3H),0.089(s,3H),0.0614(s,3H).LC-MS (ESI-TOF):calcd for[C20H40O5Si2+H]+417.24,found 417.24
Embodiment 3：Compound VI preparation
Compound V (100g, 0.24mol) is dissolved in dry 1000mL dichloromethane, addition DMAP (5.0g, 40.9mmol) with TCDI (64g, 0.36mol), rear keeping temperature is added dropwise and reacts to TLC observation raw material spot disappearances, adds water It is quenched, filters, ethyl acetate extraction, merges organic phase, saturation NaCl is washed, anhydrous Na2SO4Dry, be concentrated to give red crude product.Silicon Plastic column chromatography obtains 107g colorless oil compound VI, yield 85%.
1HNMR(400MHz,CDCl3):7.04(1H,s),7.65(1H,s,),8.36(1H,s)；6.75(s,1H),
4.40 (d, 1H, J=12.1Hz), 4.05 (d, 1H, J=3.1Hz), 3.83 (m, 1H), 3.75 (s, 3H), 2.49 (dd, 1H, J=14.1Hz), 2.26 (d, 2H, J=6.1Hz), 0.885 (s, 9H), 0.855 (s, 9H), 0.125 (s, 3H), 0.114(s,3H),0.089(s,3H),0.0614(s,3H)LC-MS(ESI-TOF):calcd for[C24H42N2O5SSi2]+ 526.24,found526.24
Embodiment 4：Compound VII preparation
Compound VI (94.9g, 0.174mol) and potassium dihydrogen phosphate (76.6g, 0.879mol) are dissolved in 2.5L ethylene glycol In monomethyl ether solvent, it is heated to flowing back, the 200mL second two of AIBN (5.7g, 34.7mmol) and triethylamine (0.174mol) is added dropwise Alcohol monomethyl ether solution, is maintained the reflux for after being added dropwise, and TLC observes raw material spot and disappeared after 2 hours, and reaction finishes.Add saturation The NH4Cl aqueous solution is quenched, and is extracted with ethyl acetate, and merges organic phase, and saturation NaCl is washed, anhydrous Na2SO4Dry, be concentrated to give thick Product.Silica gel column chromatography obtains compound VII 61g.Yield is 84%.
1HNMR(400MHz,CDCl3):6.79(m,1H),4.54(m,1H),4.19(m,1H),3.83(m,1H),3.75 (s, 3H), 2.49 (dd, 1H, J=14.1Hz), 2.26 (d, 2H, J=6.1Hz), 1.69 (ddd, 1H, J=12.9, J=6.4, J =2.8Hz), 1.81 (ddd, 1H, J=12.9, J=7.9, J=4.9Hz), 0.885 (s, 9H), 0.855 (s, 9H), 0.125 (s,3H),0.114(s,3H),0.089(s,3H),0.0614(s,3H)LC-MS(ESI-TOF):calcd for [C20H40O4Si2]+400.24,found 400.24
Embodiment 5：Compound VIII preparation
Under room temperature noble gas atmosphere, acetylacetone,2,4-pentanedione is added into compound VII (80g, 0.2mol) 800mL dichloromethane solutions Vanadyl (2g, 7.35mmol), after stirring 30min, tert-Butanol peroxide (50ml, 0.5mol) is added, it is anti-that backflow is warming up to after finishing Answer 10 hours.TLC observation raw material spots disappear, and reaction finishes, and is down to room temperature, add the Na2SO3 aqueous solution and are quenched, ethyl acetate Extraction, merge organic phase, the saturation NaCl aqueous solution is washed, anhydrous Na2SO4Dry, be concentrated to give yellow oil crude product.Crude product silicon Plastic column chromatography obtains 67.6g colorless oil VIII, yield 85%.
1HNMR(400MHz,CDCl3):4.54(m,1H),4.19(m,1H),3.83(m,1H),3.75(s,3H),3.35 (m, 1H), 2.49 (dd, 1H, J=14.1Hz), 2.26 (d, 2H, J=6.1Hz), 1.69 (ddd, 1H, J=12.9, J=6.4, J =2.8Hz), 1.81 (ddd, 1H, J=12.9, J=7.9, J=4.9Hz), 0.885 (s, 9H), 0.855 (s, 9H), 0.125 (s,3H),0.114(s,3H),0.089(s,3H),0.0614(s,3H)LC-MS(ESI-TOF):calcd for [C20H40O5Si2]+416.24,found 416.24
Embodiment 6：Compound IX preparation
Compound VIII (85g, 0.1mol) is dissolved in 800mL ether, is cooled to -78 DEG C, add AlLiH4 (19g, 0.5mol), after keeping temperature is reacted 4 hours for -78 DEG C after adding, TLC observation raw material spots disappear, and add 200mL methanol to quench Go out reaction, concentration of reaction solution adds the dissolving of 1L ethyl acetate, filtering, and filtrate is concentrated to give crude product.Silica gel column chromatography obtains compound IX 75g, yield 87%.
1HNMR(400MHz,CDCl3):δ=4.58 (1H, s), 4.42-4.26 (2H, m), 3.44-3.28 (2H, m), 2.21 (1H, dd, J=8.5,4.5Hz), 2.10-1.85 (3H, m), 1.50-1.36 (2H, m), 1.27 (1H, dd, J=12.5, 11.0Hz),0.92(9H,s),0.90(9H,s),0.13(3H,s),0.12(3H,s),0.09(6H,s)；LC-MS(ESI- TOF):calcd for[C19H42O4Si2]+390.26,found 390.26.
Embodiment 7：Compound X preparation
Compound IX (40g, 102.6mmol) is dissolved in THF (600mL), is cooled to 0 DEG C, be added dropwise sodium metaperiodate (86g, 406mmol) aqueous solution 200ml, freely it is warmed to room temperature, and continues after reacting 12 hours after being added dropwise, TLC observation raw material spots Disappear, add water quenching to go out reaction, ethyl acetate extraction, merging organic phase, the saturation NaCl aqueous solution washes, anhydrous Na2SO4Dry, concentration Obtain brown crude product.Silica gel column chromatography obtains 29.6g compound X, yield 87%.
1HNMR(400MHz,CDCl3):δ=4.34 (2H, m), 2.55 (2H, dd, J=14.0,4.0Hz), 2.35 (2H, Ddd, J=14.0,7.0,1.0Hz), 1.94 (2H, t, J=5.5Hz), 0.87 (18H, s), 0.07 (6H, s), 0.06 (6H, s)； LC-MS(ESI-TOF):calcd for[C18H38O3Si2]+358.24,found 358.24.
Embodiment 8：Compound XI preparation
Trimethyl silicane ethyl (15.7g, 98.3mmol) is dissolved in 500mL anhydrous THF, nitrogen protection, and It is cooled to -78 DEG C.Be slowly added dropwise into above-mentioned reaction solution instill LDA (100mL, 1.0M) THF solution, after being added dropwise- Continue reaction 30 minutes at 78 DEG C.Compound X (14g, 39.3mmol) is dissolved in the anhydrous THF of 50mL and is slowly dropped into reaction solution In, -78 DEG C are kept after being added dropwise and is reacted 1 hour, TLC observation raw material spots disappear, and reaction finishes, and adds NH4The Cl aqueous solution It is quenched, ethyl acetate extraction, merges organic phase, the saturation NaCl aqueous solution is washed, anhydrous Na2SO4Dry, be concentrated to give brown crude product.Slightly Product silica gel column chromatography obtains 15.64g off-white color grease, yield 80%.
1HNMR(400MHz,CDCl3):δ=5.70 (1H, s), 4.20-4.08 (4H, m), 3.06 (1H, dd, J=13.5, 6.0Hz), 2.79 (1H, dd, J=13.5,3.5Hz), 2.40 (1H, dd, J=13.0,3.5Hz), 2.16 (1H, dd, J= ), 13.0,8.0Hz 1.88-1.78 (1H, m), 1.76-1.66 (1H, m), 1.28 (3H, t, J=7.0Hz), 0.88 (9H, s), 0.86(9H,s),0.06(12H,m)；LC-MS(ESI-TOF):calcd for[C21H42O4Si2]+414.26,found 414.26.
Embodiment 9：Compound II preparation
Compound XI (49g, 118.3mmol) is dissolved in 600mL THF solution, is cooled to 0 DEG C, nitrogen protection.Slowly DIBAL-H toluene solution (195mL, 1.0M) is instilled, reaction 1 hour is warmed to room temperature after being added dropwise.TLC observes raw material spot Disappear, reaction finishes, and adds NH4The Cl aqueous solution is quenched, and ethyl acetate extraction, merges organic phase, the saturation NaCl aqueous solution is washed, nothing Water Na2SO4Dry, be concentrated to give light yellow crude product.Crude product obtains the compound II of 41g colorless oils with silica gel column chromatography, and yield is 90%.
1HNMR(400MHz,CDCl3):δ=5.60 (1H, t, J=7.0Hz), 4.18-4.10 (2H, m), 4.06-3.96 (2H, m), 2.40-2.30 (2H, m), 2.18 (1H, dd, J=13.5,3.0Hz), 2.06 (1H, dd, J=12.0,9.0Hz), 1.87–1.78(1H,m),1.69–1.59(1H,m),1.43(1H,br s),0.89(18H,s),0.07(6H,s),0.06(3H, s),0.05(3H,s)；LC-MS(ESI-TOF):calcd for[C20H42O3Si2]+386.27,found 386.27
Embodiment 10：Compound I preparation
By compound II (38.6g, 0.1mol) be dissolved in 500mL drying DMF in, add pyridine (31.6g, 0.4mol) and Anhydrous Lithium chloride (17g, 0.4mol), 0 DEG C is cooled to, adds mesyl chloride (23g, 0.2mol), stir 2h, TLC is detected without original Material is remaining, adds 500mL water quenchings and goes out, is extracted with methyl tertiary butyl ether(MTBE), dries concentration desiccation compound III, adds what 500mL was dried THF dissolves.At 0 DEG C, n-BuLi (200mL, 0.5mol) is added into diphenylphosphine (93g, 0.5mol) THF solution, 30min is stirred, compound III THF solution is added dropwise in reaction solution, stirs 3h, TLC detections add water, stirring without raw material 20min, 200mL 30%H2O2 stirring 2h, extraction are added, drying is concentrated to give crude product, and silica gel column chromatography obtains compound I 45.6g, yield 80%.
1HNMR(400MHz,CDCl3):δ=7.71-7.58 (4H, m), 7.46-7.33 (6H, m), 5.22 (1H, ddd, J= ), 14.0,7.0,7.0Hz 3.91 (2H, m), 3.11 (1H, ddd, J=15.0,8.0,8.0Hz), 2.99 (1H, ddd, J_15.0, ), 8.0,8.0Hz 2.22-2.12 (1H, m), 2.00-1.79 (3H, m), 1.60 (2H, dd, J=5.0,5.0Hz), 0.80 (9H, s),0.78(9H,s),0.04(3H,s),0.05(6H,s),0.06(3H,s)；LC-MS(ESI-TOF):calcd for [C32H51O3PSi2]+570.31,found 570.31
Embodiment 11：Compound IV preparation
Compound IV preparation method is with embodiment 1, except that the concentration of shikimic acid in ethanol is 0.02g/mL, The mol ratio of shikimic acid and chloroacetic chloride is 1:1, reaction yield 90%.
Embodiment 12：Compound V preparation
Compound V preparation method with embodiment 2, except that compound IV, TBAB, DMAP and TBDMSCl mol ratio is 1:0.3:0.1:The concentration of 5, compound IV in DMF is that 0.5mol/L reaction yields are 90%.
Embodiment 13：Compound VI preparation
Compound VI preparation method is with embodiment 3, except that compound V, DMAP and N, N'- sulphur The mol ratio of carbonyl dimidazoles is 1:0.5:1.5；Concentration of the compound V in dichloromethane is 0.5mol/L, and reaction is received Rate is 80%.
Embodiment 14：Compound VII preparation
Compound VII preparation method is with embodiment 4, except that compound VI, potassium dihydrogen phosphate, AIBN and three second The mol ratio of amine is 1:3:0.1:1, reaction yield 80%.
Embodiment 15：Compound VIII preparation
Compound VIII preparation method is with embodiment 5, except that compound VII, tert-Butanol peroxide and levulinic The mol ratio of ketone vanadyl is 1:2:The concentration of 0.03, compound VII in dichloromethane is that 0.2mol/L reaction yields are 83%.
Embodiment 16：Compound IX preparation
Compound IX preparation method is with embodiment 6, except that the mol ratio of the compound VIII and AlLiH4 For 1:The concentration of 4, compound VII in ether is 0.2mol/L, reaction yield 85%.
Embodiment 17：Compound X preparation
Compound X preparation method is with embodiment 7, except that the mol ratio of the compound IX and sodium metaperiodate is 1:The concentration of 3, the compound IX in the organic solvent is 0.2mol/L.

Claims (10)

1. a kind of preparation method of paricalcitol intermediate, it is characterised in that comprise the steps of：
1) shikimic acid is in the presence of chloroacetic chloride, and alkylol R1OH reacts, and shikimate IV is made,
2) compound IV in organic solvent, under phase transfer catalyst and catalyst action, under alkalescence condition, and chlorosilane reagent R2Cl reacts, and compound V is made,
3) in organic solvent, under condensing agent effect, with N, compound VI is made in the reaction of N'- thiocarbonyldiimidazoles to compound V,
4) compound VI removes thiocarbonyl ester and obtains compound VII,
5) compound VII in organic solvent, under pro-oxidant effect, reacts with vanadyl acetylacetonate, compound VIII is made,
6) compound VIII in organic solvent, under reducing agent effect, is reduced obtained compound IX,
7) compound IX is dissolved in organic solvent, adds the aqueous solution of sodium metaperiodate, reacted and compound X is made,
Wherein R1For methyl either ethyl or isopropyl, R2For silicon ethers protection group.
2. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that in step 1, the alkylol R1One or more of the OH in methanol, ethanol or isopropanol, the shikimic acid is in alkylol R1Concentration in OH for 0.1~ 0.02g/mL, the mol ratio 1 of the shikimic acid and chloroacetic chloride:1~1:1.2.
3. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that described organic molten in step 2 Agent is selected from acetonitrile, dichloromethane, tetrahydrofuran, DMF, dioxane, ethyl acetate, the one or more in toluene；The alkali Selected from triethylamine, the one or more in tri-n-butylamine or DBU；The phase transfer catalyst is selected from tetramethyl amine bromide, four Butyl amine bromide or benzyl triethyl ammonium amine bromide；The catalyst is DMAP；The chlorosilane reagent R2Cl is selected From tert-butyl chloro-silicane, tert-butyl diphenyl chlorosilane or chlorotriethyl silane.
4. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that in step 2, the compound IV, alkali, phase transfer catalyst, the mol ratio of catalyst and chlorosilane reagent are 1:0.1:0.1:3 to 1:0.3:0.3:5.
5. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that described organic molten in step 3 One or more of the agent in dichloromethane, chloroform or acetonitrile；The condensing agent is selected from DMAP or pyridine.
6. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that in step 3, the compound The mol ratio of V, condensing agent and N, N'- thiocarbonyldiimidazole is 1:0.5:1.2 to 1:1:3.
7. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that in step 4, the removing bag Include following steps：Compound VI and potassium dihydrogen phosphate are dissolved in organic solvent, are heated under counterflow condition, AIBN and three is added dropwise Solution of the ethamine in the organic solvent, react complete to compound VI reactions；The organic solvent is selected from ethylene glycol list first Ether or glycol dimethyl ether, or the mixing of two kinds of solvents；The compound VI, potassium dihydrogen phosphate, AIBN and triethylamine rub You are than being 1:3:0.1:1 to 1:7:0.3:1.5.
8. a kind of preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that described to help in step 5 Oxidant is tertbutanol peroxide or hydrogen peroxide；The organic solvent is dichloromethane or chloroform；Compound VII, help oxygen Agent and the mol ratio of vanadyl acetylacetonate are 1:2:0.03 to 1:3:0.05, compound VII concentration are 0.2~0.25mol/ L。
9. a kind of preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that described to go back in step 6 Former agent is lithium aluminium hydride reduction, and the organic solvent is one or more in ether, tetrahydrofuran or methyl tertiary butyl ether(MTBE), describedization The mol ratio of compound VIII and reducing agent is 1:4 to 1:8, compound VIII concentration are 0.1~0.15mol/L.
10. the preparation method of paricalcitol intermediate as claimed in claim 1, it is characterised in that described organic in step 7 Solvent is THF or dioxane, and the mol ratio of the compound IX and sodium metaperiodate are 1:3 to 1:6, compound IX concentration For 0.1~0.2mol/L.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586642A (en) * 2018-05-17 2018-09-28 浙江大学 A method of thioester group in removing polymer emulsion containing thioester group

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2069374A1 (en) * 1991-05-28 1992-11-29 Hector F. Deluca Synthesis of 19-nor vitamin d compounds
WO2006093290A1 (en) * 2005-03-04 2006-09-08 Tokyo Medical And Dental University 9-substituted-19-norvitamin d derivative
WO2007131364A1 (en) * 2006-05-16 2007-11-22 Mcgill University Hybrid molecules having mixed vitamin d receptor agonism and histone deacetylase inhibitory properties

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2069374A1 (en) * 1991-05-28 1992-11-29 Hector F. Deluca Synthesis of 19-nor vitamin d compounds
WO2006093290A1 (en) * 2005-03-04 2006-09-08 Tokyo Medical And Dental University 9-substituted-19-norvitamin d derivative
WO2007131364A1 (en) * 2006-05-16 2007-11-22 Mcgill University Hybrid molecules having mixed vitamin d receptor agonism and histone deacetylase inhibitory properties

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586642A (en) * 2018-05-17 2018-09-28 浙江大学 A method of thioester group in removing polymer emulsion containing thioester group

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