CN114805158B - Method for preparing calcitriol - Google Patents
Method for preparing calcitriol Download PDFInfo
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- CN114805158B CN114805158B CN202210434638.0A CN202210434638A CN114805158B CN 114805158 B CN114805158 B CN 114805158B CN 202210434638 A CN202210434638 A CN 202210434638A CN 114805158 B CN114805158 B CN 114805158B
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- 235000020964 calcitriol Nutrition 0.000 title claims abstract description 42
- 239000011612 calcitriol Substances 0.000 title claims abstract description 42
- 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 42
- 229960005084 calcitriol Drugs 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000000926 separation method Methods 0.000 claims abstract description 21
- 238000005917 acylation reaction Methods 0.000 claims abstract description 16
- 238000000746 purification Methods 0.000 claims abstract description 16
- 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 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 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 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 32
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 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
- 238000003756 stirring Methods 0.000 claims description 22
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- 238000007127 saponification reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 239000012429 reaction media Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000011084 recovery Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 238000004237 preparative chromatography Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 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
- 239000000543 intermediate Substances 0.000 abstract description 6
- 230000010933 acylation Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 15
- 238000001291 vacuum drying Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction 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
- 230000006837 decompression Effects 0.000 description 3
- 230000000694 effects Effects 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
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 238000013375 chromatographic separation Methods 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
- 238000005286 illumination Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 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
- 238000005303 weighing Methods 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
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products 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-XFEUOLMDSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 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
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 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
- 125000000524 functional group Chemical group 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 238000005342 ion exchange Methods 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
- 238000011068 loading method Methods 0.000 description 1
- 230000014759 maintenance of location Effects 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
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 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
- 201000003868 postsurgical hypothyroidism Diseases 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
- 239000000376 reactant Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 201000006409 renal osteodystrophy Diseases 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
- 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
- 239000007858 starting material Substances 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 208000030402 vitamin D-dependent rickets Diseases 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- 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 by 25-OH-VD 3 Is used as raw material to prepare 1-OH-25-ester-3, 5-ring-VD by acylation, cyclization and oxidation 3 Then acylating, ring recovering, purifying, separating, saponifying and crystallizing to obtain calcitriol. The method has the advantages of easily available raw materials, convenient operation, mild reaction conditions, environmental protection, overcoming of instability of intermediates, reduction of complicated steps of intermediate separation, purification and the like, 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 calcitriol.
Background
Vitamin D 3 Can promote calcium and phosphorus absorption, prevent and treat rickets, stimulate osteoblast and bone salt deposition, and make bone stronger. Vitamin D 3 Is inactive and has to pass through the liver to form 25-hydroxy vitamin D by adding hydroxy group at 25 position 3 Then adding a hydroxyl group on the 1 alpha position of the mixture through the kidney to form 1,25- (OH) 2 -VD 3 Namely calcitriol, has the structural formula:
。
calcitriol can be used for treating renal osteodystrophy, postoperative hypothyroidism, idiopathic or pseudo hypothyroidism, vitamin D dependent rickets, etc. in postmenopausal and senile osteoporosis, chronic renal failure patients. The calcitriol has more chiral centers in the molecular structure, huge number of stereoisomers, unstable property, sensitivity to light, heat and air, more reaction processes and similar polarities among isomers, so that the purity of synthesis is difficult to grasp.
Vitamin D is used in the existing literature of calcitriol synthesis 2 For raw materials, sulfur dioxide (SO 2 ) Isomerizing it with SO 2 Protecting conjugated double bond, oxidizing with ozone, connecting branched chain, isomerizing to cis-form product via illumination, and removing protecting group to obtain target product. The final yield of the method is 17.1%, 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 Can cause harm to the environment. The patent with publication number CN101607931A discloses a preparation method of calcitriol, which takes calcitriol as a raw material, removes most of impurities generated in the chemical reaction process through medium-pressure liquid chromatography, and performs tosylation and ring closure on the calcitriol, and removes impurities through medium-pressure liquid chromatography; and (3) carrying out oxidation reaction on the product, separating and removing impurities by using a medium-pressure chromatographic column, carrying out ring opening, then feeding a medium-pressure liquid phase to coarsely separate stereoisomers, and finally separating by using a high-pressure liquid phase chromatography to obtain the product, and carrying out hydrolysis refining to obtain calcitriol. Although calcitriol with higher purity can be obtained by the method, in the extraction process of ethyl acetate, the ethyl acetate is easy to combine with calcitriol to form crystalline solvates, so that the solvent residue after crystallization and filtration does not reach the standard, and the chromatographic separation steps are more, so that the yield of the product is easy to be low.
In recent years, with the diversification of calcitriol functions, the market demand for calcitriol is increasing, and a method for synthesizing calcitriol with high purity is urgently needed by manufacturers.
Disclosure of Invention
Based on the disadvantages of the prior art, the object of the present invention is to provide a process for preparing calcitriol by 25-OH-VD 3 The calcitriol is prepared by a series of reactions under mild conditions, is convenient to operate, has high product purity and is suitable for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method of preparing calcitriol comprising the steps of:
by 25-OH-VD 3 Synthesis of VD by acylation with tosyl chloride (I) as starting Material 3 -3, 25-p-toluenesulfonic acid diester; will VD 3 Cyclization reaction of-3, 25-p-toluenesulfonic acid diester and anhydrous sodium carbonate to synthesize 25-ester-3, 5-ring-VD 3 Then synthesizing 1-OH-25-ester-3, 5-ring-VD through oxidation reaction 3 ；
1-OH-25-ester-3, 5-Ring-VD 3 With acetic anhydride to synthesize 1-acetyl-25-ester-3, 5-ring-VD 3 Then ring recovery is carried out 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 The method comprises the steps of carrying out a first treatment on the surface of the And then saponifying and crystallizing to obtain calcitriol.
The raw materials used in the method are all common commercial products.
The method for preparing calcitriol comprises the following synthetic routes:
the invention firstly uses 25-OH-VD 3 1-OH-25-ester-3, 5-ring-VD 3 is prepared by acylation, cyclization and oxidation, and high-purity calcitriol is obtained by acylation, ring recovery, purification, separation, saponification and crystallization, and each step of reaction can be carried out at normal temperature, so that the requirements on equipment are low, the operation is convenient, and the thermal isomerization of intermediates is avoided; the crude products are continuously reacted in the first steps, so that the production period is saved, the steps of separation and purification are reduced, and the yield is improved; by adjusting reactants and synthetic routes, the defects of environmental pollution caused by harmful gases, equipment corrosion caused by strong oxidants and the like are avoided. The method has the advantages of easily obtained raw materials, convenient operation, mild reaction conditions, environmental protection, overcoming the instability of the intermediate, reducing the separation of the intermediate,The purification and other complicated steps have the characteristics of single product, high yield and suitability for industrial production.
Drawings
FIG. 1 is a synthetic process scheme of the present invention.
Description of the embodiments
In order to make the technical objects, technical solutions and advantageous effects of the present invention more apparent, the technical solutions of the present invention will be further described with reference to specific examples, which are intended to illustrate the present invention but are not to be construed as limiting the present invention, and specific techniques or conditions are not specified in the examples, and are performed according to techniques or conditions described in the literature in the art or according to the product specifications.
A method of preparing calcitriol, as shown in fig. 1, comprising the steps of:
(1) Acylation reaction (I)
N-hexane is used as a reaction medium, and 25-OH-VD is added into the n-hexane under the protection of nitrogen 3 （C 27 H 44 O 2 The method comprises the steps of carrying out a first treatment on the surface of the Molecular weight (mw) 400.64) and p-toluenesulfonyl chloride (C) 7 H 7 ClO 2 S, S; mw 190.65), stirring to react, protecting 3-and 25-hydroxyl groups to generate VD 3 -3, 25-para-toluenesulfonic acid diester (C) 41 H 56 O 6 S 2 The method comprises the steps of carrying out a first treatment on the surface of the mw 709.02), as formula (I); washing with water in ice bath to remove p-toluenesulfonyl chloride, p-toluenesulfonic acid and hydrochloric acid, standing for layering, concentrating n-hexane phase under reduced pressure to remove solvent 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 catalyst 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; 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
To methanol (CH) 4 O; mw 32.04) to add VD 3 -3, 25-para-toluenesulfonic acid diester and anhydrous sodium carbonate (Na 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the mw 105.99), stirring for reaction, and cyclizing the 3-position and the 5-position of the ring A, wherein the reaction is shown as a formula (III); then extracting with n-hexane, concentrating under reduced pressure to remove solvent to obtain 25-ester-3, 5-ring-VD 3 （C 35 H 52 O 4 S；mw568.87）。
The 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 the VD 3 The molar ratio of the 3, 25-para-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
Adding 25-ester-3, 5-ring-VD with methylene dichloride as reaction solvent 3 Adding selenium dioxide (SeO) 2 The method comprises the steps of carrying out a first treatment on the surface of the mw 110.96) is used as an oxidant, and the mixture is stirred for reaction, and under the action of a selenium dioxide oxidant, 25-ester-3, 5-ring-VD 3 Introducing a hydroxyl group into the 1 position of the catalyst, and reacting the catalyst with the formula (IV); adding potassium hydroxide to remove excessive oxidant, washing with water, separating solid from 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 reactions (formula (V)):
SeO 2 (mw110.96) + 2KOH (mw56.11)==H 2 O(mw18.01) + K 2 SeO 3 (Potassium selenite, mw 205.17)
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 the catalyst is 0.1-0.35 mol/L; the drying condition is that the temperature is 40-55 ℃ and vacuum or inert gas is adopted for protection.
(4) Acylation reaction (II)
N-hexane is used as a reaction medium, and 1-OH-25-ester-3, 5-ring-VD is added into the n-hexane under the protection of nitrogen 3 Acetic anhydride (C) 4 H 6 O 3 The method comprises the steps of carrying out a first treatment on the surface of the mw 102.09), stirring and reacting, wherein the hydroxyl at the 1-position is protected, and 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 from liquid, and 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 The molar ratio of acetic anhydride is 11-10 parts; 1-OH-25-ester-3, 5-Ring-VD in n-Hexane 3 The addition amount of the catalyst is 0.1-0.5 mol/L; the drying condition is that the temperature is 40-55 ℃ and vacuum or inert gas is adopted for protection.
(5) Ring rehabilitation
Under the protection of nitrogen, adding 1-acetyl-25-ester-3, 5-ring-VD into the mixed solution of dioxane and water 3 Para-toluene sulfonic acid (C) 7 H 8 O 3 S, S; mw 172.2), stirring to react, and opening 3 and 5 rings to recover, wherein the reaction is shown as a formula (VIII); adding sodium carbonate to neutralize excess p-toluene sulfonic acid, as in formula (IX); then extracting with n-hexane, concentrating under reduced pressure, 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 reactions (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-toluene sulfonate, mw 194.19)
+ CO 2 (mw44.01)+ H 2 O(mw18.01)
The mixed solution of the dioxane and the water is formed by mixing the dioxane and the water according to the volume ratio of 1:1-10; the 1-acetyl-25-ester-3-OH-VD 3 The molar ratio of the p-toluenesulfonic acid is 1:0.1-10; 1-acetyl-25-ester-3-OH-VD in mixed solution of dioxane and water 3 The addition amount of the catalyst 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 its ratio 0.01%), and separating with preparative chromatography (reversed-phase octadecyl bonded silica gel column)The mobile phase is methanol aqueous solution-acetonitrile, the flow rate is 1.5 mL/min, the column temperature is 25-35 ℃, the target component is collected, and then reduced pressure concentration desolventizing (the temperature is 35-50 ℃ and the vacuum pressure is less than or equal to-0.05 MPa) is carried out, so that cis-1-acetyl-25-ester-3-OH-VD is obtained 3 （C 36 H 52 O 6 S；mw612.88）。
The previous 5 steps of reactions are not refined and purified, and the silica gel column in the step has relatively high requirements on silica gel during separation and purification, and substances with relatively similar polarities are difficult to separate because the silica gel is not alkali-resistant and has limited adsorption performance. Therefore, the silica gel column is separated and purified by loading 150 g activated silica gel (200-300 meshes) into the column, and the activated silica gel is treated by the following steps:
(a) Placing 300 g silica gel in 1000 mL of 5-7 mol/L hydrochloric acid, stirring and refluxing for 5-7 h at 40-60 ℃, washing to be neutral, drying the water content by controlling, 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 1000 mL n-hexane under the protection of nitrogen, adding 80-120 mL of gamma-aminopropyl trimethoxysilane, heating to 50-70 ℃, stirring for 10-14 hours, then carrying out solid-liquid separation, taking the solid, washing with n-hexane, ethanol and water respectively, drying the water by controlling, and carrying out vacuum drying at 90-120 ℃ for 3-5 hours to obtain silanized silica gel;
(c) Weighing 300-g silanized silica gel, dispersing the silica gel in 1000-mL methanol, adding 60-80 mL of ethylenediamine, reacting for 20-26 hours at 60-80 ℃, then carrying out solid-liquid separation, washing the solid with methanol, and carrying out vacuum drying at 90-120 ℃ for 3-5 hours to obtain aminated silica gel;
(d) 300 g silanized silica gel and 15-45 g aluminum trichloride are weighed and added into 1000 mL methanol, after stirring for 20-26 h, solid-liquid separation is carried out, and the solid is taken out and dried for 3-5 h at 90-120 ℃ in vacuum, thus obtaining activated silica gel (Al) 3+ Modified silica gel).
The initial state of the silica gel surface has low activity, and the functional groups are difficult to combine with the silica gel surface, the treatment steps enable the silica gel surface to expose a large amount of silicon hydroxyl groups through acidification, and then ethylenediamine is coupled and grafted to the silica gel surface through the bridging effect of gamma-aminopropyl trimethoxy silane, so that the alkali resistance of the silica gel is improvedThen go through Al 3+ Coordination modification improves the ion exchange and affinity capability of the activated silica gel, greatly enhances the adsorption performance of alkaline and dissociable substances, and is not easy to cause dead adsorption.
(7) Saponification and crystallization
Methanol is taken as a reaction medium, and cis-1-acetyl-25-ester-3-OH-VD is added into the methanol under the protection of nitrogen 3 And potassium hydroxide, stirring to react, and removing protecting groups at 1-position and 25-position to obtain 1,25- (OH) 2 -VD 3 （C 27 H 44 O 3 The method comprises the steps of carrying out a first treatment on the surface of the mw 416.64), the reaction is as in formula (X); neutralizing the excess potassium hydroxide with hydrochloric acid, as in formula (XI); concentrating (the concentration is carried out until the amount of the solvent removed is 50-80% of the amount of the methanol), extracting with n-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, mw 210.32)
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 the catalyst is 0.1-0.5 mol/L; during the extraction of the n-hexane, the dosage of the n-hexane is 5-50 times of that of a product obtained after saponification and concentration; the crystallization is carried out in the normal hexane extract, the crystallization temperature is-15-30 ℃ and the 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 all common commercial products.
Example 1
A method of preparing calcitriol comprising the steps of:
(1) Acylation reaction (I)
10.0 g of 25-OH-VD is added to 100mL of n-hexane under nitrogen 3 (25.0 mmol) and 10.50 g p-toluenesulfonyl chloride (55.1 mmol), stirred for reaction 4. 4 h; washing with water for 3-4 times under ice bath condition, standing for layering, collecting n-hexane phase, concentrating under reduced pressure at 50deg.C and vacuum pressure of less than or equal to-0.05 MPa, and desolventizing to obtain 17.72 gVD 3 -3, 25-p-toluenesulfonic acid diester.
(2) Cyclization reaction
Adding the VD obtained in the step (1) into 250mL of methanol under the protection of nitrogen 3 -3, 25-para-toluenesulfonic acid diester (25.0 mmol) with 1.40 g anhydrous sodium carbonate (13.2 mmol), stirred for 6 h; then extracting with n-hexane for 2-3 times, combining the extracts, concentrating under reduced pressure at 50 ℃ and vacuum pressure of less than or equal to-0.05 MPa to remove solvent to obtain 13.94 g of 25-ester-3, 5-ring-VD 3 。
(3) Oxidation reaction
Adding the 25-ester-3, 5-ring-VD obtained in the step (2) to 200mL of dichloromethane 3 (24.5 mmol) and 2.50 g selenium dioxide (22.5 mmol), stirring to react 2 h; adding 15 mL volume percent of 10 percent potassium hydroxide solution, stirring for 30 min, washing until the pH value of the final washing liquid is 7-8, separating solid from liquid, taking solid, and vacuum drying at 50 ℃ to obtain 13.20 g of 1-OH-25-ester-3, 5-ring-VD 3 。
(4) Acylation reaction (II)
Adding the step (3) 1-OH-25-ester-3, 5-ring-VD into 75mL of n-hexane under the protection of nitrogen 3 (23.88 mmol) and 5mL acetic anhydride, stirring reaction 8h; sodium carbonate was added to neutralize excess acetic anhydride (sodium carbonate solution was added until no gas was generated); washing with water for 3-4 times, separating solid from liquid, taking solid, and vacuum drying at 45 ℃ to obtain 14.20 g of 1-acetyl-25-ester-3, 5-ring-VD 3 。
(5) Ring rehabilitation
Under the protection of nitrogen, adding the 1-acetyl-25-ester-3, 5-ring-VD obtained in the step (4) into 200mL of mixed solution of dioxane and water (the mixed solution of dioxane and water is prepared by mixing the dioxane and the water uniformly according to the volume ratio of 3:7) 3 (23.87 mmol)3.25 g p-toluenesulfonic acid (18.87 mmol acts as a catalyst), stirring reaction 4 h; sodium carbonate was added to neutralize excess p-toluenesulfonic acid (sodium carbonate solution was added until no gas was generated); then extracting with n-hexane for 2-3 times, combining the extracts, concentrating under reduced pressure at 50 ℃ and vacuum pressure less than or equal to-0.05 MPa to remove solvent to obtain 14.52 g of 1-acetyl-25-ester-3-OH-VD 3 。
(6) Separation and purification
1-acetyl-25-ester-3-OH-VD obtained in step (5) 3 Dissolving in n-hexane (the amount of n-hexane is such that 1-acetyl-25-ester-3-OH-VD 3 Separating and purifying by silica gel column (eluent is n-hexane-ethanol (99:1), adding formic acid to make the volume ratio of formic acid in eluent be 0.01%), separating by preparative chromatography (reverse phase octadecyl bonded silica gel column, mobile phase is methanol water solution-acetonitrile gradient elution, flow rate is 1.5 mL/min, column temperature is 30 deg.C, detection wavelength is 265 nm), collecting target component, concentrating under reduced pressure to remove solvent (temperature is 35-50deg.C, vacuum pressure is less than or equal to-0.05 MPa), obtaining 9.80 g cis-1-acetyl-25-ester-3-OH-VD) 3 。
Wherein, the silica gel column separation and purification adopts 150 g activated silica gel (200-300 meshes) to pack the column, and the treatment steps of the activated silica gel are as follows:
(a) Placing 300 g silica gel in 1000 mL of 6 mol/L hydrochloric acid, stirring and refluxing 6 h at 50 ℃, washing with water to be neutral, drying water, and vacuum drying 4 h at 130 ℃ to obtain acidified silica gel;
(b) Dispersing the acidified silica gel obtained in the step (a) in 1000 mL n-hexane under the protection of nitrogen, adding 100mL gamma-aminopropyl trimethoxysilane, heating to 60 ℃ and stirring for 12 hours, then carrying out solid-liquid separation, taking the solid, washing with n-hexane, ethanol and water respectively, drying the water by control, and carrying out vacuum drying at 100 ℃ for 4 h to obtain silanized silica gel;
(c) 300 g silanized silica gel is weighed and dispersed in 1000 mL methanol, 66 mL ethylenediamine is added to react at 70 ℃ for 24 h, then solid-liquid separation is carried out, the solid is taken and washed by methanol, and 4 h is dried in vacuum at 100 ℃ to obtain aminated silica gel;
(d) Weighing 300 g silanized silica gel and 30 g aluminum trichloride, adding into 1000 mL methanol, stirring for 24, 24 h, separating solid from liquid, vacuum drying at 90deg.C for 4, 4 h to obtain activated silica gel (Al) 3+ Modified silica gel).
Mobile phase A is 40% methanol aqueous solution and mobile phase B is acetonitrile during preparation chromatographic separation, and the mobile phase A and the mobile phase B are subjected to the following gradient elution procedure (volume ratio of mobile phase A to mobile phase B): the volume ratio of mobile phase A to mobile phase B is kept 80:20 unchanged within 0-5 minutes; (2) The volume ratio of the mobile phase A to the mobile phase B gradually changes 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 gradually changes 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 remained constant at 40:60 over 25-30 minutes.
After separation and purification by an activated silica gel column, no other impurities exist, and the gradient elution is used for eluting 1-acetyl-25-ester-3-OH-VD 3 Good peak appearance, cis-1-acetyl-25-ester-3-OH-VD 3 Is 13.533 min, has an area of 352237. Mu.V/s and a height of 27992. Mu.V; trans 1-acetyl-25-ester-3-OH-VD 3 The retention time of (2) was 17.191 min, 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 methanol under the protection of nitrogen 3 (15.99 mmol) and 2.0 g potassium hydroxide (35.65 mmol), stirring to react 2 h; neutralizing excessive potassium hydroxide with 10% hydrochloric acid, concentrating to remove 60-80 mL of solvent, extracting with 300-mL n-hexane for 3 times, mixing the extractive solutions, and 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 calcitriol comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring recovery, separation and purification, saponification and crystallization; wherein the steps are carried out according to the process parameters of example 1 except for saponificationAnd (5) controlling. The saponification described in example 2 is mainly modified in that: 8.98/g Potassium hydroxide (160.0 mmol) was varied, the others were unchanged, and 1,25- (OH) having a purity of 99.3% was finally obtained 2 -VD 3 The yield was 58.0%.
In example 2, the amount of potassium hydroxide added was increased as compared with example 1, and the purity of the product was slightly lowered, and the yield was reduced.
Example 3
A method of preparing calcitriol comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring recovery, separation and purification, saponification and crystallization; wherein the process parameters of example 1 were controlled except for crystallization. The main changes in the crystallization described in example 3 are: 8.98/g Potassium hydroxide (160.0 mmol) was varied, the others were unchanged, and 1,25- (OH) having a purity of 99.7% was finally obtained 2 -VD 3 The yield was 62.1%.
Compared with example 1, example 3 mainly changes in that: the crystallization temperature is reduced to 0-5 ℃, the crystallization time is shortened to 12-h, and the purity of the product is slightly improved and the yield is increased.
Example 4
A method of preparing calcitriol comprising the steps of: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring recovery, separation and purification, saponification and crystallization; wherein, other steps are controlled according to the technological parameters of the embodiment 1 except for separation and purification. Compared with example 1, the separation and purification described in example 4 is mainly modified in that: non-activated silica gel was used. Finally obtaining the 1,25- (OH) with the purity of 98 percent 2 -VD 3 The yield was 51.4%.
In general, examples 1-4 all effectively synthesize calcitriol, have high purity and high yield, are economical and feasible, and examples 1-3 adopt activated silica gel for separation and purification, so that the yield can be better improved.
Claims (9)
1. A method of preparing calcitriol, comprising the steps of:
by 25-OH-VD 3 As starting materialWith tosyl chloride to synthesize VD 3 -3, 25-p-toluenesulfonic acid diester; will VD 3 Cyclization reaction of-3, 25-p-toluenesulfonic acid diester and anhydrous sodium carbonate to synthesize 25-ester-3, 5-ring-VD 3 Then synthesizing 1-OH-25-ester-3, 5-ring-VD through oxidation reaction 3 ；
1-OH-25-ester-3, 5-Ring-VD 3 With acetic anhydride to synthesize 1-acetyl-25-ester-3, 5-ring-VD 3 Then ring recovery is carried out 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 The method comprises the steps of carrying out a first treatment on the surface of the Then saponifying and crystallizing to obtain calcitriol;
the synthetic route for calcitriol is shown below:
2. the process for the preparation of calcitriol according to claim 1, characterized in that the acylation reaction (I) is in particular: n-hexane is used as a reaction medium, and 25-OH-VD is added into the n-hexane under the protection of nitrogen 3 And p-toluenesulfonyl chloride, stirring and reacting for 0.5-5 hours; washing with water at-5~0 deg.C, standing for layering, concentrating n-hexane phase under reduced pressure, and desolventizing to obtain VD 3 -3, 25-p-toluenesulfonic acid diester;
wherein the 25-OH-VD 3 The molar ratio of the catalyst 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 according to claim 1, characterized in that the cyclisation reaction is in particular: adding VD into methanol under the protection of nitrogen 3 Stirring and reacting the 3, 25-para-toluenesulfonic acid diester with anhydrous sodium carbonate for 0.5-10 hours, extracting with n-hexane, concentrating under reduced pressure and desolventizing to obtain 25-ester-3, 5-ring-VD 3 ；
Wherein the VD 3 The molar ratio of the 3, 25-para-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 according to claim 1, characterized in that the oxidation reaction is specifically: adding 25-ester-3, 5-ring-VD into methylene dichloride as reaction medium 3 Adding selenium dioxide as an oxidant, stirring for reaction for 0.5-10 hours, adding potassium hydroxide to remove excessive oxidant, washing with water, separating solid from liquid, and drying the solid 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 the catalyst is 0.1-0.35 mol/L.
5. The process for the preparation of calcitriol according to claim 1, characterized in that the acylation reaction (II) is in particular: n-hexane is used as a reaction medium, and 1-OH-25-ester-3, 5-ring-VD is added into the n-hexane under the protection of nitrogen 3 And acetic anhydride, stirring and reacting for 0.5-24 hours, adding sodium carbonate to neutralize excessive acetic anhydride, washing with water, separating solid from liquid, and drying the solid to obtain 1-acetyl-25-ester-3, 5-ring-VD 3 ；
Wherein the 1-OH-25-ester-3, 5-ring-VD 3 The molar ratio of the acetic anhydride is 1:1-10; 1-OH-25-ester-3, 5-Ring-VD in n-Hexane 3 The addition amount of the catalyst is 0.1-0.5 mol/L.
6. The method for preparing calcitriol according to claim 1, characterized in that the ring reversion is specifically: 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 and reacting for 0.5-10 hours, adding sodium carbonate to neutralize excessive p-toluenesulfonic acid, extracting by normal hexane, concentrating under reduced pressure and desolventizing to obtain 1-acetyl-25-ester-3-OH-VD 3 ；
Wherein,the mixed solution of the dioxane and the water is formed by mixing the dioxane and the water according to the volume ratio of 1:1-10; the 1-acetyl-25-ester-3-OH-VD 3 The molar ratio of the p-toluenesulfonic acid is 1:0.1-10; 1-acetyl-25-ester-3-OH-VD in mixed solution of dioxane and water 3 The addition amount of the catalyst is 0.1-0.5 mol/L.
7. The method for preparing calcitriol according to claim 1, wherein the separation and purification are specifically as follows: 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 component, concentrating under reduced pressure, and removing solvent to obtain cis-1-acetyl-25-ester-3-OH-VD 3 。
8. The method for preparing calcitriol according to claim 1, characterized in that the saponification is in particular: methanol is taken as a reaction medium, and cis-1-acetyl-25-ester-3-OH-VD is added into the methanol under the protection of nitrogen 3 And potassium hydroxide, after stirring and reacting for 0.5-24 hours, neutralizing excessive potassium hydroxide by hydrochloric acid, and concentrating in vacuum;
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 the catalyst is 0.1-0.5 mol/L.
9. The method for preparing calcitriol according to claim 8, characterized in that the crystallization is specifically: and extracting the product obtained by saponification with n-hexane, directly crystallizing with n-hexane at-15-30 ℃ for 5-48 hours, filtering, and drying in vacuum to obtain calcitriol.
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