CN114805158A - Method for preparing high-purity calcitriol - Google Patents
Method for preparing high-purity calcitriol Download PDFInfo
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- 235000020964 calcitriol Nutrition 0.000 title claims abstract description 40
- 239000011612 calcitriol Substances 0.000 title claims abstract description 40
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 title claims abstract description 40
- 229960005084 calcitriol Drugs 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000926 separation method Methods 0.000 claims abstract description 28
- 238000005917 acylation reaction Methods 0.000 claims abstract description 19
- 238000000746 purification Methods 0.000 claims abstract description 17
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 238000007127 saponification reaction Methods 0.000 claims abstract description 12
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 41
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- 239000000741 silica gel Substances 0.000 claims description 28
- 229910002027 silica gel Inorganic materials 0.000 claims description 28
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 239000012429 reaction media Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
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- 238000004237 preparative chromatography Methods 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 2
- KFPMLWUKHQMEBU-UHFFFAOYSA-N 3-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC(S(Cl)(=O)=O)=C1 KFPMLWUKHQMEBU-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000010933 acylation Effects 0.000 abstract description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- SJECZPVISLOESU-UHFFFAOYSA-N 3-trimethoxysilylpropan-1-amine Chemical compound CO[Si](OC)(OC)CCCN SJECZPVISLOESU-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical group CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 2
- JWUBBDSIWDLEOM-XHQRYOPUSA-N (3e)-3-[(2e)-2-[1-(6-hydroxy-6-methylheptan-2-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2\C1=C\C=C1/CC(O)CCC1=C JWUBBDSIWDLEOM-XHQRYOPUSA-N 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000013725 Chronic Kidney Disease-Mineral and Bone disease Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- RNGFNLJMTFPHBS-UHFFFAOYSA-L dipotassium;selenite Chemical compound [K+].[K+].[O-][Se]([O-])=O RNGFNLJMTFPHBS-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- GHKGUEZUGFJUEJ-UHFFFAOYSA-M potassium;4-methylbenzenesulfonate Chemical compound [K+].CC1=CC=C(S([O-])(=O)=O)C=C1 GHKGUEZUGFJUEJ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 201000006409 renal osteodystrophy Diseases 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 208000030402 vitamin D-dependent rickets Diseases 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity calcitriol, which is implemented by using 25-OH-VD 3 Preparing 1-OH-25-ester-3, 5-ring-VD by acylation, cyclization and oxidation 3 And then acylation, ring restoration, purification, separation, saponification and crystallization are carried out to prepare calcitriol. The method has the advantages of easily available raw materials, convenient operation, mild reaction conditions, environmental protection, overcoming the instability of the intermediate, reducing the complicated steps of intermediate separation, purification and the like, along with single product, high yield and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a method for preparing high-purity calcitriol.
Background
Vitamin D 3 Can promote absorption of calcium and phosphorus, prevent and treat rickets, stimulate osteoblast and bone salt deposition, and make bone firmer. Vitamin D 3 Without activity, 25-hydroxyvitamin D must be formed by adding hydroxyl groups to the 25-position of the liver 3 Then, a hydroxyl group is added to the 1 alpha position of the compound through the kidney to form 1,25- (OH) 2 -VD 3 I.e. boneThe chemical triol has the structural formula:
calcitriol can be used for treating postmenopausal osteoporosis, senile osteoporosis, renal osteodystrophy of chronic renal failure patients, postoperative thyroid hypofunction, idiopathic or pseudothyroid hypofunction, vitamin D dependent rickets, etc. The calcitriol has more chiral centers in the molecular structure, large number of stereoisomers, unstable properties, sensitivity to light, heat and air, and particularly has more reaction processes and similar polarities among isomers, so that the synthetic purity is difficult to master.
The existing literature, the synthesis of calcitriol, uses vitamin D 2 Using sulfur dioxide (SO) as raw material 2 ) Isomerizing it with SO 2 Protecting conjugated double bond, ozone oxidizing, grafting branched chain, light irradiating to isomerize into cis product, and eliminating protecting group to obtain the target product. The final yield of the method is 17.1 percent, but because the intermediate and the product are sensitive to illumination, the product can be uncontrollably changed by the irradiation of a high-pressure mercury lamp, and SO is used in the reaction 2 It is harmful to the environment. The patent with publication number CN101607931A discloses a preparation method of calcitriol, which uses calcitriol as a raw material, removes most impurities generated in the chemical reaction process by medium-pressure liquid chromatography, and removes impurities by the calcitriol through tosylation and ring closure of the calcitriol and the medium-pressure liquid chromatography; and (3) carrying out oxidation reaction on the product, carrying out separation and impurity removal by using a medium-pressure chromatographic column, carrying out ring opening, roughly separating a stereoisomer by using a medium-pressure liquid phase, and finally carrying out high-pressure liquid-phase chromatographic separation to obtain a product, and hydrolyzing and refining the product to obtain calcitriol. Although the method can obtain the calcitriol with higher purity, in the extraction process of the ethyl acetate, the ethyl acetate is easy to combine with the calcitriol to form a crystallized solvate, so that the residual solvent amount after crystallization and filtration does not reach the standard, and the chromatographic separation steps are multiple, so that the low product yield is easily caused.
In recent years, with the diversification of calcitriol functions, the demand of calcitriol in the market is increasing, and a method for synthesizing high-purity calcitriol is urgently needed by production enterprises.
Disclosure of Invention
Based on the defects of the prior art, the invention aims to provide a method for preparing high-purity calcitriol in a 25-OH-VD mode 3 The calcitriol is prepared from the raw materials through a series of reactions with mild conditions, is convenient to operate, has high product purity, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method of preparing high purity calcitriol, comprising the steps of:
at 25-OH-VD 3 Is used as a starting material to be subjected to acylation reaction (I) with tosyl chloride to synthesize VD 3 -3, 25-p-toluenesulfonic acid diester; VD is 3 Cyclizing reaction of-3, 25-p-toluenesulfonic acid diester and anhydrous sodium carbonate to synthesize 25-ester-3, 5-ring-VD 3 Then the 1-OH-25-ester-3, 5-ring-VD is synthesized by oxidation reaction 3 ；
1-OH-25-ester-3, 5-ring-VD 3 Acylation reaction with acetic anhydride (II) to synthesize 1-acetyl-25-ester-3, 5-ring-VD 3 Then ring-recovering under the action of p-toluenesulfonic acid to synthesize 1-acetyl-25-ester-3-OH-VD 3 ；
1-acetyl-25-ester-3-OH-VD 3 The cis-1-acetyl-25-ester-3-OH-VD is obtained by separation and purification 3 (ii) a Then saponifying and crystallizing to obtain calcitriol.
The raw materials used in the method are all common commercial products.
The method for preparing the high-purity calcitriol has the following synthetic route:
the invention firstly uses 25-OH-VD 3 Preparing 1-OH-25-ester-3, 5-ring-VD 3 by acylation, cyclization and oxidation, and obtaining high-purity calcitriol by acylation, ring restoration, purification, separation, saponification and crystallizationThe reaction can be carried out at normal temperature, the requirement on equipment is not high, the operation is convenient, and the thermal isomerization of an intermediate is avoided; the former reaction steps adopt crude products to continue the reaction, thereby saving the production period, reducing the steps of separation and purification and improving the yield; by adjusting reactants and a synthetic route, the defects of environmental pollution caused by harmful gas, equipment corrosion caused by strong oxidant and the like are avoided. The method has the advantages of easily available raw materials, convenient operation, mild reaction conditions, environmental protection, overcoming the instability of the intermediate, reducing the complicated steps of intermediate separation, purification and the like, and having the characteristics of single product, high yield and suitability for industrial production.
Drawings
FIG. 1 is a scheme of the synthesis process of the present invention.
Detailed Description
In order to make the technical purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention are further described with reference to specific examples, which are intended to explain the present invention and are not to be construed as limiting the present invention, and those who do not specify a specific technique or condition in the examples follow the techniques or conditions described in the literature in the art or follow the product specification.
A method for preparing high-purity calcitriol, as shown in fig. 1, comprising the steps of:
(1) acylation reaction (I)
Adding 25-OH-VD into n-hexane under the protection of nitrogen by taking n-hexane as a reaction medium 3 (C 27 H 44 O 2 (ii) a Molecular weight (mw)400.64) and p-toluenesulfonyl chloride (C) 7 H 7 ClO 2 S; mw 190.65), stirring, protecting hydroxyl groups at 3-position and 25-position to generate VD 3 3, 25-P-toluenesulfonic acid diester (C) 41 H 56 O 6 S 2 (ii) a mw709.02), formula (I); washing with water in ice bath to remove p-toluenesulfonyl chloride, p-toluenesulfonic acid and hydrochloric acid, as formula (II), standing for layering, concentrating n-hexane phase under reduced pressure, and desolventizing to obtain VD 3 3, 25-p-toluenesulfonic acid diester.
Main reaction (formula (I)):
C 27 H 44 O 2 (mw400.64)+2C 7 H 7 ClO 2 S(mw190.65)＝＝C 41 H 56 O 6 S 2 (mw709.02)+2HCl(mw36.46)
side reactions (formula (II)):
C 7 H 7 ClO 2 S(mw190.65)+H 2 O(mw18.01)＝＝C 7 H 8 O 3 s (p-toluenesulfonic acid, mw172.2) + HCl (mw36.46)
Wherein, the 25-OH-VD 3 The molar ratio of the p-toluenesulfonyl chloride to the p-toluenesulfonyl chloride is 1: 2-10; 25-OH-VD in n-hexane 3 The adding amount is 0.1-0.5 mol/L; the conditions of decompression concentration and desolventizing are that the temperature is 40-60 ℃ and the vacuum pressure is less than or equal to-0.05 MPa.
(2) Cyclization reaction
Under the protection of nitrogen, methanol (CH) 4 O; mw32.04) with VD 3 Bis (ester) -3, 25-p-toluenesulfonate with anhydrous sodium carbonate (Na) 2 CO 3 (ii) a mw105.99), stirring to react, and cyclizing the 3-position and the 5-position of the A ring, wherein the reaction is shown as the formula (III); then extracting with n-hexane, and obtaining 25-ester-3, 5-ring-VD by decompression concentration and desolventization 3 (C 35 H 52 O 4 S；mw568.87)。
Reaction (formula (III)):
2C 41 H 56 O 6 S 2 (mw709.02)+2CH 4 O(mw32.04)+Na 2 CO 3 (mw105.99)＝＝2C 35 H 52 O 4 S(mw568.87)+H 2 O(mw18.01)+CO 2 (mw44.01)+2C 7 H 7 O 3 SNa(mw194.18)
wherein, said VD 3 The molar ratio of the-3, 25-p-toluenesulfonic acid diester to the anhydrous sodium carbonate is 1: 0.5-5; VD in methanol 3 The addition amount of the-3, 25-p-toluenesulfonic acid diester is 0.1-0.2 mol/L; the conditions of decompression concentration and desolventizing are that the temperature is 40-60 ℃ and the vacuum pressure is less than or equal to-0.05 MPa.
(3) Oxidation reaction
Taking dichloromethane as a reaction solvent, adding 25-ester-3, 5-ring-VD 3 Then adding selenium dioxide (SeO) 2 (ii) a mw 110.96) as oxidant, stirring for reaction, and reacting under the action of selenium dioxide oxidant to obtain 25-ester-3, 5-ring-VD 3 Introducing a hydroxyl group at the 1-position, and reacting according to a formula (IV); adding potassium hydroxide to remove excessive oxidant, such as formula (V), washing, separating solid and liquid, and drying to obtain 1-OH-25-ester-3, 5-ring-VD 3 (C 34 H 48 O 4 S；mw552.83)。
Main reaction (formula (IV)):
2C 35 H 52 O 4 S(mw568.87)+SeO 2 (mw110.96)＝＝2C 34 H 48 O 4 S(mw552.83)+Se(mw78.96)+2CH 4 O(mw32.04)
side reaction (formula (V)):
SeO 2 (mw110.96)+2KOH(mw56.11)＝＝H 2 O(mw18.01)+K 2 SeO 3 (Potassium selenite, mw205.17)
Wherein the 25-ester-3, 5-ring-VD 3 The molar ratio of the selenium dioxide to the selenium dioxide is 1: 0.5-5; 25-ester-3, 5-Ring-VD in dichloromethane 3 The addition amount of (A) is 0.1-0.35 mol/L; the drying condition is that the temperature is 40-55 ℃ and vacuum or inert gas protection is adopted.
(4) Acylation reaction (II)
Taking n-hexane as a reaction medium, and adding 1-OH-25-ester-3, 5-ring-VD into the n-hexane under the protection of nitrogen 3 And acetic anhydride (C) 4 H 6 O 3 (ii) a mw102.09), stirring for reaction, and protecting the hydroxyl at the 1-position, wherein the reaction is shown as a formula (VI); adding sodium carbonate to neutralize excess acetic anhydride, as in formula (VII); washing with water, separating solid and liquid, drying to obtain 1-acetyl-25-ester-3, 5-ring-VD 3 (C 36 H 50 O 5 S；mw594.87)。
Main reaction (formula (VI)):
C 34 H 48 O 4 S(mw552.83)+C 4 H 6 O 3 (mw102.09)＝＝C 36 H 50 O 5 S(mw594.87)+C 2 H 4 O 2 (mw60.05)
side reactions (formula (VII)):
C 4 H 6 O 3 (mw102.09)+Na 2 CO 3 (mw105.99)＝＝2C 2 H 3 O 2 na (sodium acetate, mw 82.04) + CO 2 (mw44.01)
Wherein the 1-OH-25-ester-3, 5-Ring-VD 3 And the molar ratio of acetic anhydride is 1: 1-10; 1-OH-25-ester-3, 5-Ring-VD in n-Hexane 3 The addition amount of (A) is 0.1-0.5 mol/L; the drying condition is that the temperature is 40-55 ℃ and vacuum or inert gas protection is adopted.
(5) Ring restoration
Adding 1-acetyl-25-ester-3, 5-ring-VD into the mixed solution of dioxane and water under the protection of nitrogen 3 And p-toluenesulfonic acid (C) 7 H 8 O 3 S; mw172.2), stirring for reaction, and opening and recovering 3 and 5 rings, wherein the reaction is shown as a formula (VIII); adding sodium carbonate to neutralize excess p-toluenesulfonic acid, as in formula (IX); then extracting by normal hexane, decompressing, concentrating and desolventizing to obtain 1-acetyl-25-ester-3-OH-VD 3 (C 36 H 52 O 6 S；mw612.88)。
Main reaction (formula (VIII)):
C 36 H 50 O 5 S(mw594.87)+H 2 O(mw18.01)＝＝C 36 H 52 O 6 S(mw612.88)
side reaction (formula (IX)):
2C 7 H 8 O 3 S(mw172.2)+Na 2 CO 3 (mw105.99)＝＝2C 7 H 7 O 3 SNa (sodium p-toluenesulfonate, mw194.19) + CO 2 (mw44.01)+H 2 O(mw18.01)
Wherein the mixed solution of dioxane and water is prepared by mixing dioxane and water according to the volume ratio of 1: 1-10; the 1-acetyl-25-ester-3-OH-VD 3 And the molar ratio of p-toluenesulfonic acid is 1: 0.1-10; 1-acetyl-25-ester-3-OH-VD in a mixture of dioxane and water 3 The addition amount of (A) is 0.1-0.5 mol/L; the conditions of decompression concentration and desolventizing are that the temperature is 40-60 ℃ and the vacuum pressure is less than or equal to-0.05 MPa.
(6) Separation and purification
1-acetyl-25-ester-3-OH-VD 3 Dissolving in n-hexane, separating and purifying with silica gel column (eluent is n-hexane-ethanol (99:1), adding formic acid to make it account for 0.01%), separating with preparative chromatography (reverse octadecyl bonded silica gel chromatographic column, mobile phase is methanol water solution-acetonitrile, flow rate is 1.5mL/min, column temperature is 25-35 deg.C), collecting target components, concentrating under reduced pressure, desolventizing (temperature is 35-50 deg.C, vacuum pressure is less than or equal to-0.05 MPa), to obtain cis-1-acetyl-25-ester-3-OH-VD 3 (C 36 H 52 O 6 S；mw612.88)。
The previous 5 steps of reactions are not refined and purified, the silica gel column separation and purification of the step has relatively high requirements on silica gel, and substances with relatively close polarities are difficult to separate due to the fact that the silica gel is not alkali-resistant and has limited adsorption performance. Therefore, the silica gel column is separated and purified by adopting 150g of activated silica gel (200-300 meshes) filled in the column, and the treatment steps of the activated silica gel are as follows:
(a) placing 300g of silica gel in 1000mL of 5-7 mol/L hydrochloric acid, stirring and refluxing for 5-7 h at 40-60 ℃, washing with water to be neutral, draining water, and vacuum drying for 3-5 h at 110-140 ℃ to obtain acidified silica gel;
(b) dispersing the acidified silica gel obtained in the step (a) in 1000mL of n-hexane under the protection of nitrogen, adding 80-120 mL of gamma-aminopropyltrimethoxysilane, heating to 50-70 ℃, stirring for 10-14 hours, then carrying out solid-liquid separation, taking the solid, respectively washing with n-hexane, ethanol and water, controlling the water content, and carrying out vacuum drying at 90-120 ℃ for 3-5 hours to obtain silanized silica gel;
(c) weighing 300g of silanized silica gel, dispersing in 1000mL of methanol, adding 60-80 mL of ethylenediamine, reacting at 60-80 ℃ for 20-26 h, then carrying out solid-liquid separation, washing the solid with methanol, and vacuum drying at 90-120 ℃ for 3-5 h to obtain aminated silica gel;
(d) weighing 300g of silanized silica gel and 15-45 g of aluminum trichloride, adding the silanized silica gel and the aluminum trichloride into 1000mL of methanol, stirring for 20-26 h, performing solid-liquid separation, and vacuum drying the solid at 90-120 ℃ for 3-5 h to obtain activated silica gel (Al) 3+ Modified silica gel).
Initial shape of silica gel surfaceThe activity of the state is low, the functional group is difficult to combine with the silica gel, the treatment step exposes a large amount of silicon hydroxyl on the surface of the silica gel through acidification, then the ethylenediamine is coupled and grafted on the surface of the silica gel through the bridging action of gamma-aminopropyltrimethoxysilane, the alkali resistance of the silica gel is improved, and finally the Al is used for 3+ The coordination modification improves the ion exchange and affinity capacity of the activated silica gel, greatly enhances the adsorption performance to alkality and dissociable substances, and is not easy to cause dead adsorption.
(7) Saponification and crystallization
Methanol is taken as a reaction medium, under the protection of nitrogen, cis-1-acetyl-25-ester-3-OH-VD is added into the methanol 3 And potassium hydroxide, stirring for reaction, and removing protecting groups at 1-position and 25-position to obtain 1,25- (OH) 2 -VD 3 (C 27 H 44 O 3 (ii) a mw416.64) according to formula (X); neutralizing excess potassium hydroxide with hydrochloric acid, as in formula (XI); concentrating (concentrating until the amount of the desolvation is 50-80% of the amount of the methanol), extracting by using normal hexane, crystallizing, filtering, and drying in vacuum to obtain 1,25- (OH) 2 -VD 3 。
Main reaction (formula (X)):
C 36 H 52 O 6 S(mw612.88)+2KOH(mw56.11)＝＝C 27 H 44 O 3 (mw416.64)+C 2 H 3 O 2 K(mw98.14)+C 7 H 7 O 3 SK (Potassium p-toluenesulfonate, mw210.32)
Side reactions (formula (XI)):
KOH(mw56.11)+HCl(mw36.46)＝＝KCl(mw74.56)+H 2 O(mw18.01)
wherein the cis-1-acetyl-25-ester-3-OH-VD 3 And the molar ratio of potassium hydroxide is 1: 2-20; cis-1-acetyl-25-ester-3-OH-VD in methanol 3 The addition amount of (A) is 0.1-0.5 mol/L; during the extraction of the n-hexane, the amount of the n-hexane is 5-50 times of that of a product obtained after saponification and concentration; the crystallization is carried out in a normal hexane extract, the crystallization temperature is-15-30 ℃, and the crystallization time is 5-48 h; the temperature of the vacuum drying is controlled to be 30-45 ℃.
The raw materials and instruments used in the method are common commercial products.
Example 1
A method of preparing high purity calcitriol, comprising the steps of:
(1) acylation reaction (I)
Under the protection of nitrogen, 10.0g of 25-OH-VD is added into 100mL of n-hexane 3 (25.0mmol) and 10.50g of p-toluenesulfonyl chloride (55.1mmol) are stirred for reaction for 4 hours; washing with water for 3-4 times under ice bath condition, standing for layering, taking n-hexane phase, concentrating under reduced pressure at 50 deg.C and vacuum pressure of less than or equal to-0.05 MPa, and desolventizing to obtain 17.72gVD 3 -3, 25-p-toluenesulfonic acid diester.
(2) Cyclization reaction
Adding VD obtained in step (1) into 250mL of methanol under the protection of nitrogen 3 Reacting 3, 25-p-toluenesulfonic acid diester (25.0mmol) with 1.40g of anhydrous sodium carbonate (13.2mmol) by stirring for 6 hours; then extracting with n-hexane for 2-3 times, combining the extracts, concentrating under reduced pressure at 50 deg.C and vacuum pressure less than or equal to-0.05 MPa for desolventizing to obtain 13.94g of 25-ester-3, 5-ring-VD 3 。
(3) Oxidation reaction
Adding the 25-ester-3, 5-ring-VD obtained in step (2) to 200mL of dichloromethane 3 (24.5mmol) and 2.50g selenium dioxide (22.5mmol), stirring and reacting for 2 h; adding 15mL of 10 volume percent potassium hydroxide solution, stirring for 30min, washing until the pH of the last washing liquid is 7-8, performing solid-liquid separation, taking the solid, and drying in vacuum at 50 ℃ to obtain 13.20g of 1-OH-25-ester-3, 5-ring-VD 3 。
(4) Acylation reaction (II)
Adding the 1-OH-25-ester-3, 5-ring-VD in the step (3) into 75mL of n-hexane under the protection of nitrogen 3 (23.88mmol) and 5mL of acetic anhydride, and stirring for reaction for 8 h; adding sodium carbonate to neutralize excess acetic anhydride (adding sodium carbonate solution until no gas is produced); washing with water for 3-4 times, performing solid-liquid separation, and vacuum drying the solid at 45 ℃ to obtain 14.20g of 1-acetyl-25-ester-3, 5-ring-VD 3 。
(5) Ring restoration
Under the protection of nitrogen, 200mL of a mixed solution of dioxane and water (dioxane and water as specified above) was addedEvenly mixed with the volume ratio of 3: 7) is added with the 1-acetyl-25-ester-3, 5-ring-VD obtained in the step (4) 3 (23.87mmol) and 3.25g of p-toluenesulfonic acid (18.87mmol plays a role of a catalyst), and stirring for reaction for 4 hours; sodium carbonate was added to neutralize excess p-toluenesulfonic acid (sodium carbonate solution was added until no gas was produced); then extracting with n-hexane for 2-3 times, combining the extract solutions, concentrating under reduced pressure at 50 ℃ and vacuum pressure less than or equal to-0.05 MPa for desolventizing to obtain 14.52g of 1-acetyl-25-ester-3-OH-VD 3 。
(6) Separation and purification
The 1-acetyl-25-ester-3-OH-VD obtained in the step (5) 3 Dissolving in n-hexane (the amount of n-hexane is 1-acetyl-25-ester-3-OH-VD) 3 Until the solution is completely dissolved), separating and purifying with silica gel column (the eluent is n-hexane-ethanol (99:1), adding formic acid to make the volume ratio of formic acid in the eluent be 0.01%), separating with preparative chromatography (reverse octadecyl bonded silica gel chromatography column, mobile phase is methanol water solution-acetonitrile gradient elution, flow rate is 1.5mL/min, column temperature is 30 deg.C, detection wavelength is 265nm), collecting target components, concentrating under reduced pressure, and desolventizing (temperature is 35-50 deg.C, vacuum pressure is less than or equal to-0.05 MPa) to obtain 9.80g of cis-1-acetyl-25-ester-3-OH-VD 3 。
Wherein, the silica gel column is separated and purified by adopting 150g of activated silica gel (200-300 meshes) to be filled into the column, and the activated silica gel comprises the following processing steps:
(a) placing 300g of silica gel in 1000mL of 6mol/L hydrochloric acid, stirring and refluxing for 6h at 50 ℃, washing to be neutral, draining, and vacuum drying for 4h at 130 ℃ to obtain acidified silica gel;
(b) dispersing the acidified silica gel obtained in the step (a) in 1000mL of n-hexane under the protection of nitrogen, adding 100mL of gamma-aminopropyltrimethoxysilane, heating to 60 ℃, stirring for 12 hours, then carrying out solid-liquid separation, washing the solid with n-hexane, ethanol and water respectively, draining the water, and carrying out vacuum drying at 100 ℃ for 4 hours to obtain silanized silica gel;
(c) weighing 300g of silanized silica gel, dispersing in 1000mL of methanol, adding 66mL of ethylenediamine, reacting at 70 ℃ for 24h, then carrying out solid-liquid separation, washing the solid with methanol, and vacuum-drying at 100 ℃ for 4h to obtain aminated silica gel;
(d) weighing 300g of silanized silica gel and 30g of aluminum trichloride, adding into 1000mL of methanol, stirring for 24h, performing solid-liquid separation, and vacuum drying the solid at 90 ℃ for 4h to obtain activated silica gel (Al) 3+ Modified silica gel).
During the preparative chromatographic separation, the mobile phase A is 40% methanol water solution, the mobile phase B is acetonitrile, and the mobile phase A and the mobile phase B are subjected to the following gradient elution procedure (volume ratio of the mobile phase A to the mobile phase B): the volume ratio of the mobile phase A to the mobile phase B is kept constant at 80:20 within 0-5 minutes; (2) the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80:20 to 60:40 at a constant speed within 5-15 minutes; (3) the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 60:40 to 40:60 at a constant speed within 15-25 minutes; (5) the volume ratio of mobile phase A to mobile phase B was kept constant at 40:60 for 25-30 minutes.
After separation and purification by activated silica gel column, no other impurities exist, the gradient elution is used, and 1-acetyl-25-ester-3-OH-VD 3 Good peak appearance, cis-1-acetyl-25-ester-3-OH-VD 3 The retention time of (a) is 13.533min, the area is 352237 muV/s, and the height is 27992 muV; trans-1-acetyl-25-ester-3-OH-VD 3 The retention time of (2) was 17.191min, the area was 62201. mu.V/s, and the height was 4007. mu.V.
(7) Saponification and crystallization
Adding the cis-1-acetyl-25-ester-3-OH-VD obtained in the step (6) into 100mL of methanol under the protection of nitrogen 3 (15.99mmol) and 2.0g potassium hydroxide (35.65mmol), stirring and reacting for 2 h; neutralizing excessive potassium hydroxide with 10% hydrochloric acid, concentrating until 60-80 mL of solvent is removed, extracting with 300mL of n-hexane for 3 times, mixing extractive solutions, and directly crystallizing with the extractive solution (at room temperature for 24 hr) to obtain 1,25- (OH) with purity of 99.6% 2 -VD 3 The yield was 60.3%.
Example 2
A method of preparing high purity calcitriol, comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring restoration, separation and purification, saponification and crystallization; wherein, except for saponification, other steps are controlled according to the process parameters of example 1. Practice ofExample 2 the main changes to saponification are: by changing 8.98g of potassium hydroxide (160.0mmol) and the others, 1,25- (OH) having a purity of 99.3% was finally obtained 2 -VD 3 The yield was 58.0%.
Compared with example 1, example 2 increases the addition amount of potassium hydroxide, and the product purity is slightly reduced, and the yield is reduced.
Example 3
A method of preparing high purity calcitriol, comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring restoration, separation and purification, saponification and crystallization; wherein, except for crystallization, other steps are controlled according to the process parameters of the embodiment 1. The main changes of the crystallization described in example 3 are: by changing 8.98g of potassium hydroxide (160.0mmol) and the others, 1,25- (OH) having a purity of 99.7% was finally obtained 2 -VD 3 The yield was 62.1%.
Compared to example 1, example 3 is mainly modified in that: the crystallization temperature is reduced to 0-5 ℃, the crystallization time is shortened to 12 hours, the product purity is slightly improved, and the yield is increased.
Example 4
A method of preparing high purity calcitriol, comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring restoration, separation and purification, saponification and crystallization; wherein, except for separation and purification, other steps are controlled according to the process parameters of the embodiment 1. Compared with example 1, the separation and purification described in example 4 mainly changes in that: silica gel without activation treatment was used. Finally obtaining the 1,25- (OH) with the purity of 98 percent 2 -VD 3 Yield 51.4%.
In general, the calcitriol is effectively synthesized in the embodiments 1 to 4, the purity and the yield are high, the method is economical and feasible, and the yield can be better improved by adopting activated silica gel for separation and purification in the embodiments 1 to 3.
Claims (9)
1. A method for preparing high-purity calcitriol, comprising the steps of:
at 25-OH-VD 3 To get upAcylation reaction of starting material with tosyl chloride (I) to synthesize VD 3 -3, 25-p-toluenesulfonic acid diester; VD is 3 Cyclization reaction of-3, 25-p-toluenesulfonic acid diester and anhydrous sodium carbonate to synthesize 25-ester-3, 5-ring-VD 3 Then the 1-OH-25-ester-3, 5-ring-VD is synthesized by oxidation reaction 3 ；
1-OH-25-ester-3, 5-ring-VD 3 Acylation reaction with acetic anhydride (II) to synthesize 1-acetyl-25-ester-3, 5-ring-VD 3 Then ring-recovering under the action of p-toluenesulfonic acid to synthesize 1-acetyl-25-ester-3-OH-VD 3 ；
1-acetyl-25-ester-3-OH-VD 3 Separating and purifying to obtain cis-1-acetyl-25-ester-3-OH-VD 3 (ii) a Then saponifying and crystallizing to obtain calcitriol.
2. The method for preparing calcitriol with high purity according to claim 1, characterized in that the acylation reaction (I) is in particular: adding 25-OH-VD into n-hexane under the protection of nitrogen by taking n-hexane as a reaction medium 3 And p-toluenesulfonyl chloride, and stirring for reaction for 0.5-5 hours; washing with water at the temperature of-5-0 ℃, standing for layering, and then taking n-hexane phase for decompression, concentration and desolventizing to obtain VD 3 -3, 25-p-toluenesulfonic acid diester;
wherein, the 25-OH-VD 3 The molar ratio of the p-toluenesulfonyl chloride to the p-toluenesulfonyl chloride is 1: 2-10; 25-OH-VD in n-hexane 3 The addition amount is 0.1-0.5 mol/L.
3. The method for preparing calcitriol with high purity according to claim 1, characterized in that the cyclization reaction is specifically: adding VD into methanol under the protection of nitrogen 3 Stirring and reacting-3, 25-p-toluenesulfonic acid diester with anhydrous sodium carbonate for 0.5-10 hours, extracting with n-hexane, and performing reduced pressure concentration and desolventization to obtain 25-ester-3, 5-cyclo-VD 3 ；
Wherein, said VD 3 The molar ratio of the-3, 25-p-toluenesulfonic acid diester to the anhydrous sodium carbonate is 1: 0.5-5; VD in methanol 3 The addition amount of the-3, 25-p-toluenesulfonic acid diester is 0.1-0.2 mol/L.
4. The method for preparing calcitriol with high purity according to claim 1, characterized in that the oxidation reaction is in particular: taking dichloromethane as a reaction medium, adding 25-ester-3, 5-ring-VD 3 Then adding selenium dioxide as an oxidant, stirring and reacting for 0.5-10 hours, adding potassium hydroxide to remove the excessive oxidant, washing, carrying out solid-liquid separation, taking the solid and drying to obtain 1-OH-25-ester-3, 5-ring-VD 3 ；
Wherein the 25-ester-3, 5-ring-VD 3 The molar ratio of the selenium dioxide to the selenium dioxide is 1: 0.5-5; 25-ester-3, 5-Ring-VD in dichloromethane 3 The addition amount of (b) is 0.1-0.35 mol/L.
5. The method for preparing calcitriol with high purity according to claim 1, characterized in that the acylation reaction (II) is in particular: adding 1-OH-25-ester-3, 5-ring-VD into n-hexane under the protection of nitrogen by using n-hexane as a reaction medium 3 And acetic anhydride, stirring for reaction for 0.5-24 hours, adding sodium carbonate to neutralize excessive acetic anhydride, washing with water, carrying out solid-liquid separation, taking out the solid, and drying to obtain 1-acetyl-25-ester-3, 5-ring-VD 3 ；
Wherein the 1-OH-25-ester-3, 5-Ring-VD 3 And acetic anhydride in a molar ratio of 1: 1-10; 1-OH-25-ester-3, 5-Ring-VD in n-Hexane 3 The addition amount of (b) is 0.1-0.5 mol/L.
6. The method for preparing calcitriol in high purity according to claim 1, characterized in that the ring reconstitution is in particular: under the protection of nitrogen, adding 1-acetyl-25-ester-3, 5-ring-VD 3 and p-toluenesulfonic acid into a mixed solution of dioxane and water, stirring for reaction for 0.5-10 hours, adding sodium carbonate to neutralize excessive p-toluenesulfonic acid, extracting by n-hexane, and performing reduced pressure concentration and desolventization to obtain 1-acetyl-25-ester-3-OH-VD 3 ；
Wherein the mixed solution of dioxane and water is prepared by mixing dioxane and water according to the volume ratio of 1: 1-10; the 1-acetyl-25-ester-3-OH-VD 3 And the molar ratio of p-toluenesulfonic acid is 1: 0.1-10; of dioxane and water1-acetyl-25-ester-3-OH-VD in the mixed solution 3 The addition amount of (b) is 0.1-0.5 mol/L.
7. The method for preparing calcitriol with high purity according to claim 1, wherein the separation and purification specifically comprises: 1-acetyl-25-ester-3-OH-VD 3 Dissolving in n-hexane, separating and purifying with silica gel column, separating with preparative chromatography, collecting target components, concentrating under reduced pressure, and desolventizing to obtain cis-1-acetyl-25-ester-3-OH-VD 3 。
8. The method for preparing calcitriol with high purity according to claim 1, characterized in that the saponification is specifically: methanol is taken as a reaction medium, cis-1-acetyl-25-ester-3-OH-VD is added into the methanol under the protection of nitrogen 3 And potassium hydroxide, stirring for reaction for 0.5-24 hours, neutralizing excessive potassium hydroxide with hydrochloric acid, and concentrating in vacuum;
wherein the cis-1-acetyl-25-ester-3-OH-VD 3 And potassium hydroxide in a molar ratio of 1: 2-20; cis-1-acetyl-25-ester-3-OH-VD in methanol 3 The addition amount of (b) is 0.1-0.5 mol/L.
9. The method for preparing calcitriol in high purity according to claim 8, characterized in that the crystallization is in particular: extracting the product obtained by saponification with n-hexane, directly crystallizing with n-hexane at-15-30 ℃ for 5-48 hours, filtering, and vacuum drying to obtain 1,25- (OH) 2 -VD 3 。
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