CN107501317B - A kind of preparation method of paricalcitol intermediate - Google Patents
A kind of preparation method of paricalcitol intermediate Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of paricalcitol intermediate, comprise the steps of after 1) being esterified shikimic acid, 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) it restores；7) it aoxidizes, finally obtains a kind of paricalcitol intermediate.Raw material of the present invention is selected as cheap and easy to get, and all chiral centres are introduced by raw material, and reaction is not related to any chiral centre, and product quality is easy to control, is conducive to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of paricalcitol intermediate.
Background technique
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 (calciferol 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 40 years by a definite date the study found that it is daily take one vitamin D can be the risk for suffering from breast cancer, colon cancer and oophoroma
Reduce half.Sunlight irradiates on the skin, and body will generate vitamin D, this some vitamin D accounts for the supply of body vitamin D
90%.
In recent years, show to be deficient in vitamin D may be extremely harmful to body for more and more evidences.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 phase is closed.
(Paricalcitol, chemical name: 19- removes -1 α of first (nor), 3 β, 25- trihydroxy -9,10- to paricalcitol
Secoergosta-5 (Z), 7 (Z), 22 (E)-triolefins；Synonym 19- removes -1 α of first, 25- dihydroxyvitamin D 2) it is activity dimension
Raw element D therapeutic agent, can be used for preventing and treating secondary hyperparathyroidism (SHPT), dialyses and transplants to receiving
The SHPT of preoperative III and IV phase chronic renal disease (CKD) patient shows prevention and treatment curative effect, it has also become dialysis is suffered from
The most widely used SHPT prevention of person and therapeutic agent, reduce parathyroid hormone (PTH) by convenient oral administration
Level, while there is minimum influence to blood calcium and serum phosphorus levels, and PTH reduction is a key finger of SHPT treatment curative effect
Mark.The structural formula of paricalcitol is shown in formula 1:
Synthesis paricalcitol there are mainly two types of method in the prior art:
Method 1 is reported by WO2008053961, JP053392300, using steroidal compounds lumisterol as starting material, synthesis
Reaction is more than 17 steps.Wherein, the Julia coupling alkylene yield used when connecting side chain is low, uses Na-Hg very not environmentally；?
Several steps reaction when converting to exocyclic double bond, selectivity is bad, as dihydroxylation may oxidized side chain it is double
Key, the route are not suitable for industrialized mass production.
Method 2 is reported by US5281731, US5086191, using the strategy of convergence, is first respectively synthesized two segments,
Then the compound of vitamin D structure is obtained in flakes again, deprotection obtains paricalcitol, which converges due to using
Poly- method reduces synthesis risk, be conducive to final products quality control, therefore paricalcitol it is a large amount of it is industrially prepared on
There is biggish advantage compared with method 1.But there is also the defects in terms of cost for the route, and hexatomic ring fragment compound X is from natural
Chinic acid, though the compound can be obtained by natural product extraction, expensive due to low output, about 1.3 ten thousand RMB are every
Kilogram, the initial cost for thus preparing compound II is very high.
In conclusion in the synthetic route of the key intermediate X of paricalcitol reported at present, there is restrictions
The factor of industrial amplification production.Therefore, the mass production of Yao Shixian paricalcitol has to find a safe and feasible
Synthetic route.
Summary of the invention
The technical problem to be solved by the present invention is providing a kind of paricalcitol key intermediate preparation side that safety is cheap
Method.
In order to solve the above technical problems, the technical solution adopted by the present invention is that:
A kind of preparation method of paricalcitol intermediate, comprises the steps of
1) shikimic acid is in the presence of chloroacetic chloride and alkylol R1OH reaction, is made shikimate IV,
2) compound IV in organic solvent, under phase transfer catalyst and catalyst action, under alkaline condition and chlorosilane
Reagent R2Cl reaction, is made compound V,
3) in organic solvent, under condensing agent effect, with N, N'- thiocarbonyldiimidazole reacts is made chemical combination to compound V
Object 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, the aqueous solution of sodium metaperiodate is added, reacted and compound X is made,
Wherein R1For methyl or ethyl or isopropyl, R2For silicon ethers protecting 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 R1OH is selected from one of methanol, ethyl alcohol or isopropanol or a variety of, preferably methanol；
The shikimic acid is in alkylol R1Concentration in OH is 0.1~0.02g/mL, the molar ratio 1:1 of the shikimic acid and chloroacetic chloride~
1:1.2.The alkylol is used as reactant and reaction dissolvent simultaneously.
In step 2, the organic solvent be selected from acetonitrile, methylene chloride, tetrahydrofuran, DMF, dioxane, ethyl acetate,
One of toluene is a variety of, preferably DMF；The alkali be selected from triethylamine, one of tri-n-butylamine or DBU or a variety of,
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 4-dimethylaminopyridine, 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, chlorosilane reagent molar ratio be 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 methylene chloride, chloroform or acetonitrile, preferably methylene chloride；The condensation
Agent is selected from 4-dimethylaminopyridine or pyridine, preferably 4-dimethylaminopyridine.
In step 3, the molar ratio of the compound V, 4-dimethylaminopyridine and N, N'- thiocarbonyldiimidazole are 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 adds the following steps are included: compound VI and potassium dihydrogen phosphate are dissolved in organic solvent
Under heat to counterflow condition, the solution of AIBN and triethylamine in the organic solvent, reaction to compound VI fully reacting is added dropwise；
The organic solvent is selected from the mixing of glycol monoethyl ether or glycol dimethyl ether or two kinds of solvents；The compound VI, phosphorus
The molar 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 methylene chloride or chloroform；Compound VII, the molar ratio of pro-oxidant and vanadyl acetylacetonate is stated as 1:2:
The concentration of 0.03 to 1:3:0.05, compound VII in the organic solvent is 0.2~0.25mol/L.
In step 6, the reducing agent used that restores is lithium aluminium hydride reduction, and the organic solvent is selected from ether, tetrahydrofuran
Or one of methyl tertiary butyl ether(MTBE) or a variety of, the molar 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 molar ratio of the compound IX and sodium metaperiodate
For 1:3 to 1:6, concentration of the compound IX in the organic solvent is 0.1~0.2mol/L.
Compound X in organic solvent, under alkaline condition, reacts with trimethyl silicane ethyl, compound can be made
XI, compound XI are reacted with DIBAL-H in organic solvent, and compound II can be made, and preparing specific method can refer to patent
Method disclosed in US5281731.
The utility model has the advantages that
1) starting material of the present invention is selected as shikimic acid cheap and easy to get, and the price of Industrial raw material is about 750 yuan of people
Every kilogram of coin is the 5~7% of prior art starting material chinic acid, and route cost is greatly reduced；
2) reagent of compound VII prepare compound VIII is tertbutanol peroxide cheap and easy to get, low in cost；
3) all chiral centres in variation route are introduced by raw material, and reaction is not related to any chiral centre, for chemical combination
The quality of object X is easy to control.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
In the present invention, Me indicates methyl；Et indicates ethyl；I-Pr indicates isopropyl；AIBN indicates azo-bis-isobutyl cyanide；
TCDI indicates 1,1 '-thio-carbonyldiimidazoles；DMAP indicates 4-dimethylaminopyridine；DIBAL-H indicates diisobutyl aluminium hydride；
THF indicates tetrahydrofuran；DMF indicates N,N-dimethylformamide；DBU indicates 1,8- diazabicylo [5.4.0] 11 carbon -7-
Alkene；TBDMSCl indicates tert-butyl chloro-silicane；TLC indicates thin-layer chromatography；
Embodiment 1: the preparation of compound IV
Shikimic acid (50g, 0.287mol) is dissolved in the dry methanol of 500mL, 0 DEG C is cooled under nitrogen protection, adds
Enter chloroacetic chloride (23.4g, 0.3mol) and warm naturally to room temperature, keeps thermotonus to TLC detection raw material spot to disappear, reacted
Finish.Reaction is quenched with water, ethyl acetate extraction, merges organic phase, saturated common salt washing, anhydrous Na2SO4It is dry, it is concentrated to give shallow
The crude product of yellow oil.Crude product obtains the compound IV 51g of 54g light yellow oil 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: the preparation of compound V
Compound IV (50g, 0.266mol) is dissolved in 200mL anhydrous DMF, (5.0g, 26.6mmol) tetrabutyl bromine is added
Change ammonium, DMAP (5.0g, 40.9mmol) and TBDMSCl (159.6g, 1.064mol), be cooled under nitrogen protection zero degree with
Under, it is added triethylamine (200g, 2.0mol), room temperature is warmed naturally to after finishing, reaction to TLC detection raw material spot disappears, instead
It should finish.Saturated aqueous ammonium chloride is added reaction is quenched, ethyl acetate extraction, merges organic phase, saturated common salt washing, nothing
Water Na2SO4It is dry, the crude product of give light yellow oil is concentrated.Crude product obtains 105.1g light yellow oil 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: the preparation of compound VI
Compound V (100g, 0.24mol) is dissolved in dry 1000mL methylene chloride, addition DMAP (5.0g,
40.9mmol) with TCDI (64g, 0.36mol), keeps thermotonus to TLC observation raw material spot to disappear after being added dropwise, add water
It is quenched, filters, ethyl acetate extraction merges organic phase, and saturation NaCl is washed, anhydrous Na2SO4It is dry, it is 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: the preparation of compound VII
Compound VI (94.9g, 0.174mol) and potassium dihydrogen phosphate (76.6g, 0.879mol) are dissolved in 2.5L ethylene glycol
It in monomethyl ether solvent, 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, maintains the reflux for after being added dropwise, and TLC observes raw material spot and disappears after 2 hours, end of reaction.Add saturation
NH4Cl aqueous solution is quenched, and is extracted with ethyl acetate, and merges organic phase, and saturation NaCl is washed, anhydrous Na2SO4It is dry, it is 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: the preparation of compound VIII
Under room temperature noble gas atmosphere, acetylacetone,2,4-pentanedione is added into the 800mL dichloromethane solution of compound VII (80g, 0.2mol)
Vanadyl (2g, 7.35mmol) after stirring 30min, is added tert-Butanol peroxide (50ml, 0.5mol), it is anti-that reflux is warming up to after finishing
It answers 10 hours.TLC observes raw material spot and disappears, and end of reaction is down to room temperature, and Na2SO3 aqueous solution is added and is quenched, ethyl acetate
Extraction merges organic phase, and saturation NaCl aqueous solution is washed, anhydrous Na2SO4It is dry, it is 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: the preparation of compound IX
Compound VIII (85g, 0.1mol) is dissolved in 800mL ether, is cooled to -78 DEG C, be added AlLiH4 (19g,
0.5mol), after keeping temperature to react 4 hours for -78 DEG C after adding, TLC observes raw material spot and disappears, and 200mL methanol is added to quench
It goes out reaction, the dissolution of 1L ethyl acetate, filtering is added in concentration of reaction solution, 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: the preparation of compound X
Compound IX (40g, 102.6mmol) is dissolved in THF (600mL), is cooled to 0 DEG C, be added dropwise sodium metaperiodate (86g,
After 406mmol) aqueous solution 200ml is freely warmed to room temperature after being added dropwise, and the reaction was continued 12 hours, TLC observes raw material spot
It disappears, adds water quenching reaction, ethyl acetate extraction merges organic phase, and saturation NaCl aqueous solution is washed, anhydrous Na2SO4It is dry, 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: the preparation of compound XI
Trimethyl silicane ethyl (15.7g, 98.3mmol) is dissolved in the anhydrous THF of 500mL, 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-
The reaction was continued at 78 DEG C 30 minutes.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, and TLC observes raw material spot and disappears, and NH is added in end of reaction4Cl aqueous solution
It is quenched, ethyl acetate extraction, merges organic phase, saturation NaCl aqueous solution is washed, anhydrous Na2SO4It is dry, it is 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: the preparation of compound II
Compound XI (49g, 118.3mmol) is dissolved in the THF solution of 600mL, is cooled to 0 DEG C, nitrogen protection.Slowly
The toluene solution (195mL, 1.0M) for instilling DIBAL-H is warmed to room temperature reaction 1 hour after being added dropwise.TLC observes raw material spot
It disappears, NH is added in end of reaction4Cl aqueous solution is quenched, ethyl acetate extraction, merges organic phase, and saturation NaCl aqueous solution is washed, nothing
Water Na2SO4It is dry, it is concentrated to give light yellow crude product.Crude product obtains the compound II of 41g colorless oil 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: the preparation of compound I
Compound II (38.6g, 0.1mol) is dissolved in the dry DMF of 500mL, be added pyridine (31.6g, 0.4mol) and
Anhydrous lithium chloride (17g, 0.4mol) is cooled to 0 DEG C, is added mesyl chloride (23g, 0.2mol), stirs 2h, and TLC is detected without original
Material residue is added 500mL water quenching and goes out, extracted with methyl tertiary butyl ether(MTBE), dry that dry compound III is concentrated, and 500mL drying is added
THF dissolution.At 0 DEG C, n-BuLi (200mL, 0.5mol) is added into the THF solution of diphenylphosphine (93g, 0.5mol),
30min is stirred, the THF solution of compound III is added dropwise in reaction solution, stirs 3h, water, stirring is added without raw material in TLC detection
20min is added 200mL 30%H2O2 and stirs 2h, extraction, and drying is concentrated to get 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: the preparation of compound IV
The preparation method is the same as that of Example 1 by compound IV, except that the concentration of shikimic acid in ethanol is 0.02g/mL,
The molar ratio of shikimic acid and chloroacetic chloride is 1:1, reaction yield 90%.
Embodiment 12: the preparation of compound V
The preparation method of compound V with embodiment 2, except that compound IV, tetrabutylammonium bromide, DMAP and
The molar ratio of TBDMSCl is 1:0.3:0.1:5, and it is 90% that concentration of the compound IV in DMF, which is 0.5mol/L reaction yield,.
Embodiment 13: the preparation of compound VI
The preparation method of compound VI is with embodiment 3, except that compound V, 4-dimethylaminopyridine and N, N'- sulphur
The molar ratio of carbonyl dimidazoles is 1:0.5:1.5；The concentration of the compound V in methylene chloride is 0.5mol/L, and reaction is received
Rate is 80%.
Embodiment 14: the preparation of compound VII
The preparation method of compound VII is with embodiment 4, except that compound VI, potassium dihydrogen phosphate, AIBN and three second
The molar ratio of amine is 1:3:0.1:1, reaction yield 80%.
Embodiment 15: the preparation of compound VIII
The preparation method of compound VIII is with embodiment 5, except that compound VII, tert-Butanol peroxide and levulinic
The molar ratio of ketone vanadyl is 1:2:0.03, and it is 83% that the concentration of compound VII in methylene chloride, which is 0.2mol/L reaction yield,.
Embodiment 16: the preparation of compound IX
The preparation method of compound IX is with embodiment 6, except that the molar ratio of the compound VIII and AlLiH4
For 1:4, concentration of the compound VII in ether is 0.2mol/L, reaction yield 85%.
Embodiment 17: the preparation of compound X
The preparation method of compound X is with embodiment 7, except that the molar ratio of the compound IX and sodium metaperiodate is
The concentration of 1:3, the compound IX in the organic solvent is 0.2mol/L.
Claims (10)
1. a kind of preparation method of paricalcitol intermediate, which is characterized in that comprise the steps of
1) shikimic acid is in the presence of chloroacetic chloride and alkylol R1OH reaction, is made shikimate IV,
2) compound IV in organic solvent, under phase transfer catalyst and catalyst action, under alkaline condition and chlorosilane reagent
R2Cl reaction, is made compound V,
3) in organic solvent, under condensing agent effect, with N, N'- thiocarbonyldiimidazole reacts is made compound VI 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, the aqueous solution of sodium metaperiodate is added, reacted and compound X is made,
Wherein R1For methyl or ethyl or isopropyl, R2For silicon ethers protecting group.
2. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that in step 1), the alkyl
Alcohol R1OH is selected from one of methanol, ethyl alcohol or isopropanol or a variety of, and the shikimic acid is in alkylol R1Concentration in OH is 0.1
Molar ratio 1:1~1:1.2 of~0.02g/mL, the shikimic acid and chloroacetic chloride.
3. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that described organic in step 2)
Solvent is selected from acetonitrile, methylene chloride, tetrahydrofuran, DMF, dioxane, ethyl acetate, one of toluene or a variety of；It is described
Alkali is selected from triethylamine, one of tri-n-butylamine or DBU or a variety of；The phase transfer catalyst be selected from tetramethyl amine bromide,
Four butyl bromation amine or benzyl triethyl ammonium amine bromide；The catalyst is 4-dimethylaminopyridine；The chlorosilane reagent R2Cl
Selected from tert-butyl chloro-silicane, tert-butyl diphenyl chlorosilane or chlorotriethyl silane.
4. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that in step 2), the chemical combination
Object IV, alkali, phase transfer catalyst, catalyst and chlorosilane reagent molar ratio be 1:0.1:0.1:3 to 1:0.3:0.3:5.
5. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that described organic in step 3)
Solvent is selected from one of methylene chloride, chloroform or acetonitrile or a variety of；The condensing agent is selected from 4-dimethylaminopyridine or pyrrole
Pyridine.
6. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that in step 3), the chemical combination
Object V, condensing agent and N, the molar ratio of N'- thiocarbonyldiimidazole are 1:0.5:1.2 to 1:1:3.
7. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that in step 4), the removing
The following steps are included: compound VI and potassium dihydrogen phosphate are dissolved in organic solvent, be heated under counterflow condition, be added dropwise AIBN and
Solution of the triethylamine in the organic solvent, reaction to compound VI fully reacting；The organic solvent is selected from ethylene glycol list
The mixing of methyl ether or glycol dimethyl ether or two kinds of solvents；The compound VI, potassium dihydrogen phosphate, AIBN and triethylamine
Molar ratio is 1:3:0.1:1 to 1:7:0.3:1.5.
8. a kind of preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that described in step 5)
Pro-oxidant is tertbutanol peroxide or hydrogen peroxide；The organic solvent is methylene chloride or chloroform；Compound VII, it helps
The molar ratio of oxidant and vanadyl acetylacetonate is 1:2:0.03 to 1:3:0.05, the concentration of compound VII is 0.2~
0.25mol/L。
9. a kind of preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that described in step 6)
Reducing agent is lithium aluminium hydride reduction, and the organic solvent is one or more in ether, tetrahydrofuran or methyl tertiary butyl ether(MTBE), described
The molar ratio of compound VIII and reducing agent is 1:4 to 1:8, and the concentration of compound VIII is 0.1~0.15mol/L.
10. the preparation method of paricalcitol intermediate as described in claim 1, which is characterized in that described organic in step 7)
Solvent is THF or dioxane, and the molar ratio of the compound IX and sodium metaperiodate is 1:3 to 1:6, the concentration of compound IX
For 0.1~0.2mol/L.
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