CN117700474A - Preparation method of 25-hydroxycholesterol - Google Patents
Preparation method of 25-hydroxycholesterol Download PDFInfo
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- CN117700474A CN117700474A CN202311691768.3A CN202311691768A CN117700474A CN 117700474 A CN117700474 A CN 117700474A CN 202311691768 A CN202311691768 A CN 202311691768A CN 117700474 A CN117700474 A CN 117700474A
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- hydroxycholesterol
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- INBGSXNNRGWLJU-ZHHJOTBYSA-N 25-hydroxycholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCCC(C)(C)O)C)[C@@]1(C)CC2 INBGSXNNRGWLJU-ZHHJOTBYSA-N 0.000 title claims abstract description 37
- INBGSXNNRGWLJU-UHFFFAOYSA-N 25epsilon-Hydroxycholesterin Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(CCCC(C)(C)O)C)C1(C)CC2 INBGSXNNRGWLJU-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 99
- 238000006243 chemical reaction Methods 0.000 claims abstract description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000001816 cooling Methods 0.000 claims abstract description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000001035 drying Methods 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000000967 suction filtration Methods 0.000 claims abstract description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 8
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- HWSRCQCLMVFRQK-UHFFFAOYSA-N chloro-(methoxymethyl)-triphenyl-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(COC)C1=CC=CC=C1 HWSRCQCLMVFRQK-UHFFFAOYSA-N 0.000 claims description 6
- LLJFNWVJKMVHIL-UHFFFAOYSA-N (2-methoxy-2-oxoethyl)phosphonic acid Chemical compound COC(=O)CP(O)(O)=O LLJFNWVJKMVHIL-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- PDYVTOWPRXYXEX-UHFFFAOYSA-M CC(C)(CC[Mg]Br)O[Si](C)(C)C Chemical compound CC(C)(CC[Mg]Br)O[Si](C)(C)C PDYVTOWPRXYXEX-UHFFFAOYSA-M 0.000 description 2
- BDCFUHIWJODVNG-UHFFFAOYSA-N Desmosterol Natural products C1C=C2CC(O)C=CC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 BDCFUHIWJODVNG-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 229960005084 calcitriol Drugs 0.000 description 2
- 235000020964 calcitriol Nutrition 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- AVSXSVCZWQODGV-DPAQBDIFSA-N desmosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC=C(C)C)C)[C@@]1(C)CC2 AVSXSVCZWQODGV-DPAQBDIFSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- -1 acrylic ester Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of 25-hydroxycholesterol, and belongs to the technical field of 25-hydroxycholesterol. The preparation method of the 25-hydroxycholesterol comprises the following steps: tetrahydrofuran and KGP-06 are mixed and cooled to below 0 ℃ under the protection of nitrogen, and then methyl magnesium chloride solution is added dropwise, and the reaction temperature is controlled below 15 ℃; continuously adding hydrochloric acid solution to obtain a first reaction solution; pouring the first reaction liquid into acid water, controlling the temperature below 40 ℃, concentrating, adding water, cooling to below 30 ℃, carrying out suction filtration, washing with water, drying to obtain a solid, adding DCM and methanol to dissolve the solid, concentrating, adding methanol to replace to be thick, and cooling and crystallizing to obtain the 25-hydroxy cholesterol. The method takes KGP-06 as a raw material to obtain 25-hydroxy cholesterol through a format reaction, the yield is up to 97%, the purity is more than 98%, and the preparation method is simple and the yield is high.
Description
Technical Field
The invention relates to the technical field of 25-hydroxycholesterol, in particular to a preparation method of 25-hydroxycholesterol.
Background
25-hydroxycholesterol has a wide range of pharmacological activities, such as antiviral, anti-inflammatory, anti-IR-damage and immunomodulation in mammalian cells, and has an important role in lipid metabolism, in particular in lipid biosynthesis and metabolism. Meanwhile, 25-hydroxycholesterol is also an important intermediate for synthesizing calcitriol, so that the calcitriol has important research value, and the existing technical difficulty is that the side chain is modified to introduce 25-hydroxy. At present, the main construction methods are of two types: the AB ring and the side chain are respectively well constructed, and then are butted through reaction; the other is to modify the side chain of cholesterol to introduce a hydroxyl group at position 25.
Patent CN112608361a discloses a method for synthesizing 25-hydroxycholesterol using Bisnoralcohol (BA) as starting material, which route is as follows:
the route bromine substitutes a large amount of lithium bromide and lithium carbonate, the bromination cost is high, in addition, the coupling of the bromides and acrylic ester, nickel chloride and zinc powder are used to generate a large amount of solid waste, pyridine is used as a solvent, and a large amount of methyl acrylate is used, so that the odor of the two is large, the environment is not friendly, and the reaction is difficult to avoid due to the chemical property that the methyl acrylate is easy to polymerize.
Patent CN114315947a discloses a method for synthesizing 25-hydroxycholesterol using Bisnoralcohol (BA) as starting material, which route is as follows:
the 3-trimethylsiloxy-3-methylbutylmagnesium bromide reagent adopted in the coupling process needs to be catalyzed by a copper lithium reagent, the dosage of the magnesium reagent exceeds 10 equivalents, the reaction can be completed, the atom economy is low, and the 3-trimethylsiloxy-3-methylbutylmagnesium bromide and the copper lithium reagent are expensive, so that the cost of the 25-hydroxycholesterol is high.
Patent CN103626821a discloses a process for preparing 25-hydroxycholesterol using 24-dehydrocholesterol as starting material, which route is as follows:
the route synthesizes the 2-hydroxy cholesterol through acylation, epoxy, ring opening and other reactions, but the yield is lower, the 24-dehydrocholesterol which is the starting material is not easy to obtain, and the purity requirement is higher, so that the cost is high and the mass production cannot be realized. Heavy metal salts are also used in the process, causing great pollution.
The prior art has the difficulty that the side chain is modified to introduce 25-position hydroxyl. At present, the main construction methods are of two types: the AB ring and the side chain are respectively well constructed, and then are butted through reaction; the other is to modify the side chain of cholesterol to introduce a hydroxyl group at position 25.
The preparation method reported at present has the defects of long route, low yield, high reagent toxicity, high price of the initial raw materials and the like. Therefore, a rapid, efficient, low-toxicity and low-cost synthetic route is needed.
Disclosure of Invention
The invention aims to overcome the technical defects, and provides a preparation method of 25-hydroxycholesterol, which solves the technical problems of longer route and low yield of the method for preparing 25-hydroxycholesterol in the prior art.
In order to achieve the technical purpose, the technical scheme of the invention provides a preparation method of 25-hydroxycholesterol, which comprises the following steps:
tetrahydrofuran and KGP-06 are mixed and cooled to below 0 ℃ under the protection of nitrogen, and then methyl magnesium chloride solution is added dropwise, and the reaction temperature is controlled below 15 ℃; after the reaction is completed, continuously adding hydrochloric acid solution to obtain a first reaction solution;
pouring the first reaction liquid into acid water, controlling the temperature below 40 ℃, concentrating, adding water, cooling to below 30 ℃, carrying out suction filtration, washing with water, drying to obtain a solid, adding DCM and methanol to dissolve the solid, concentrating, adding methanol to replace to be thick, and cooling and crystallizing to obtain the 25-hydroxy cholesterol;
the KGP-06 has the structural formula:
further, the dosage ratio of KGP-06 to the methyl magnesium chloride solution is 50g (120-130) mL, and the concentration of the methyl magnesium chloride solution is 2.5-3mol/L.
Further, the KGP-06 is prepared by the steps of:
mixing dichloromethane and methanol, adding KGP-05 and Raney nickel, introducing nitrogen for replacement, cooling to 0-5 ℃, and continuously introducing hydrogen for reaction to obtain KGP-06;
the KGP-05 has the structural formula:
further, the mass ratio of KGP-05 to Raney nickel is 100 (1-2).
Further, the KGP-05 is prepared by the steps of:
mixing tetrahydrofuran, methanol and sodium borohydride, adding anhydrous lithium chloride, cooling to-5-0 ℃ under the stirring action, adding KGP-04 for continuous reaction, obtaining a second reaction liquid after the reaction is completed, slowly adding the second reaction liquid into water, then dropwise adding glacial acetic acid to adjust the pH to 4-5, and stirring to obtain KGP-05; the KGP-04 has the structural formula:
further, the KGP-04 is prepared by the steps of: adding PTS into isopropenyl acetate under the stirring action, continuously adding KGP-03, heating to 80-85 ℃ for reflux reaction, cooling to below 10 ℃ after the reaction is completed, continuously adding triethylamine, concentrating at 45-50 ℃, adding methanol, continuously concentrating until the material is thick, cooling to 5-10 ℃ and continuously stirring to obtain KGP-04;
the KGP-03 has the structural formula:
further, the reflux reaction time is 3-4 hours.
Further, the KGP-03 is prepared by the steps of:
mixing KGP-02 with THF, adding methyl phosphonoacetate diethyl ester, adding sodium methoxide, keeping the temperature below 40 ℃ for stirring reaction until the reaction is complete, and adding water and hydrochloric acid to adjust the pH to 4-5 to obtain KGP-03;
the KGP-02 has the structural formula:
further, the KGP-02 is prepared by the steps of:
mixing (methoxymethyl) triphenyl phosphorus chloride and DMSO, adding NaH, reacting at a temperature of less than 30 ℃, adding KGP-01, performing TLC monitoring reaction at a temperature of less than 40 ℃, adding water, adding hydrochloric acid to adjust pH to 4-5, extracting a water layer with dichloro, combining organic phases, concentrating to obtain oily matter, adding acetone into the oily matter, heating to 40-45 ℃, adding water dropwise, cooling to 5-10 ℃, and stirring to obtain KGP-02;
the structural formula of the KGP-01 is as follows:
further, the mass ratio of the (methoxymethyl) triphenyl phosphorus chloride to the KGP-01 is 10 (5-6).
Compared with the prior art, the invention has the beneficial effects that: the invention mixes tetrahydrofuran and KGP-06 and reduces the temperature to below 0 ℃ under the protection of nitrogen, then drops methyl magnesium chloride solution, and controls the reaction temperature to below 15 ℃; after the reaction is completed, continuously adding hydrochloric acid solution to obtain a first reaction solution; the preparation method comprises the steps of pouring the first reaction liquid into acid water, controlling the temperature below 40 ℃, concentrating, adding water, cooling to below 30 ℃, carrying out suction filtration, washing with water, drying to obtain a solid, adding DCM and methanol to dissolve the solid, concentrating, adding methanol to replace to be thick, cooling and crystallizing to obtain the 25-hydroxycholesterol.
Drawings
FIG. 1 shows the HNMR of KGP-02 obtained in example 1 according to the present invention.
FIG. 2 is a CNMR pattern of KGP-02 prepared in example 1 of the present invention.
FIG. 3 shows the HNMR of KGP-03 obtained in example 1 according to the present invention.
FIG. 4 is a CNMR pattern of KGP-03 produced in example 1 of the present invention.
FIG. 5 shows the HNMR of KGP-04 obtained in example 1 according to the present invention.
FIG. 6 is a CNMR pattern of KGP-04 produced in example 1 of the present invention.
FIG. 7 shows the HNMR of KGP-05 obtained in example 1 according to the present invention.
FIG. 8 is a CNMR pattern of KGP-05 prepared in example 1 of the present invention.
FIG. 9 is an HPLC chart of KGP-05 produced in example 1 of the present invention.
FIG. 10 shows the HNMR of KGP-07 produced in example 1 of the present invention.
FIG. 11 is a CNMR pattern of KGP-07 produced in example 1 of the present invention.
FIG. 12 is an HPLC chart of KGP-07 produced in example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The specific embodiment provides a preparation method of 25-hydroxycholesterol, which comprises the following steps:
mixing (methoxymethyl) triphenyl phosphorus chloride and DMSO, adding NaH, reacting at a temperature of less than 30 ℃, adding KGP-01, performing TLC monitoring reaction at a temperature of less than 40 ℃, adding water, adding hydrochloric acid to adjust pH to 4-5, extracting a water layer with dichloro, combining organic phases, concentrating to obtain oily matter, adding acetone into the oily matter, heating to 40-45 ℃, adding water dropwise, cooling to 5-10 ℃, and stirring to obtain KGP-02; the mass ratio of the (methoxymethyl) triphenyl phosphorus chloride to the KGP-01 is 10 (5-6);
mixing KGP-02 with THF, adding methyl phosphonoacetate diethyl ester, adding sodium methoxide, keeping the temperature below 40 ℃ for stirring reaction until the reaction is complete, and adding water and hydrochloric acid to adjust the pH to 4-5 to obtain KGP-03;
adding PTS into isopropenyl acetate under the stirring action, continuously adding KGP-03, heating to 80-85 ℃ for reflux reaction for 3-4 hours, cooling to below 10 ℃ after the reaction is completed, continuously adding triethylamine, concentrating at 45-50 ℃, adding methanol, continuously concentrating until the materials are thick, cooling to 5-10 ℃ and continuously stirring to obtain KGP-04;
mixing tetrahydrofuran, methanol and sodium borohydride, adding anhydrous lithium chloride, cooling to-5-0 ℃ under the stirring action, adding KGP-04 for continuous reaction, obtaining a second reaction liquid after the reaction is completed, slowly adding the second reaction liquid into water, then dropwise adding glacial acetic acid to adjust the pH to 4-5, and stirring to obtain KGP-05;
mixing dichloromethane and methanol, and then adding KGP-05 and Raney nickel, wherein the mass ratio of the KGP-05 to the Raney nickel is 100 (1-2); then introducing nitrogen for replacement, then cooling to 0-5 ℃ and continuously introducing hydrogen for reaction to obtain KGP-06;
tetrahydrofuran and KGP-06 are mixed and cooled to below 0 ℃ under the protection of nitrogen, and then methyl magnesium chloride solution is added dropwise, and the reaction temperature is controlled below 15 ℃; after the reaction is completed, continuously adding hydrochloric acid solution to obtain a first reaction solution; the dosage ratio of the KGP-06 to the methyl magnesium chloride solution is 50g (120-130) mL, and the concentration of the methyl magnesium chloride solution is 2.5-3mol/L;
and pouring the first reaction liquid into acid water, controlling the temperature below 40 ℃, concentrating, adding water, cooling to below 30 ℃, carrying out suction filtration, washing with water, drying to obtain a solid, adding DCM and methanol to dissolve the solid, concentrating, adding methanol to replace to be thick, and cooling and crystallizing to obtain the 25-hydroxycholesterol (namely KGP-06).
The reaction mechanism is as follows:
we have adopted a different approach than the previous strategy: the method comprises the steps of taking bispinitol oxide as a starting material, firstly constructing a carbon chain of a side chain, carrying the carbon chain, then constructing an AB ring, after constructing the AB ring, hydrogenating, and finally constructing a 25-hydroxyl group through a format reaction, thus obtaining the 25-hydroxyl cholesterol.
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The embodiment provides a preparation method of 25-hydroxycholesterol, which comprises the following steps:
pouring (methoxymethyl) triphenyl into a reaction bottle100g of phosphorus chloride and 300ml of DMSO, 12.5g of 60% NaH is added under stirring, the system temperature is kept to be less than 30 ℃, stirring is carried out for 1h after the addition is finished, then 50g of KGP-01 is added for reaction, the system temperature is kept to be not higher than 40 ℃, and TLC monitors the reaction. Developing agent: PE: ea=4:1. After the reaction was completed, 4v water was added to quench, hydrochloric acid was added to adjust pH to 4, the aqueous layer was extracted with dichloro, the organic phases were combined, and the solvent was concentrated under reduced pressure at 40℃to give an oil. Adding 250 acetone into the oily matter, heating to 45 ℃, slowly dropwise adding 350ml of water, cooling to 5 ℃ after dropwise adding water, stirring for 30min, carrying out suction filtration, washing with water, and drying (50 ℃) to obtain KGP-02 fine product, wherein the yield is 98.8%. FIGS. 1 and 2 show the hydrogen and carbon spectra of KGP-02, respectively, as follows: 1 H NMR(400MHz,CDCl 3 )δ9.75(s,1H),5.72(s,1H),1.0-2.5(m,20H),1.19(s,3H),1.17–1.05(m,2H),1.03(m,3H),0.99–0.88(m,1H),0.77(s,3H).
13 C NMR(101MHz,CDCl 3 )δ203.22(s),199.46(s),171.31(s),123.80(s),55.83(s),55.79(s),53.68(s),50.81(s),42.54(s),39.45(s),38.55(s),35.67(s),35.57(s),33.95(s),32.85(s),31.94(s),31.51(s),28.37(s),24.08(s),20.96(s),19.95(s),17.36(s),11.95(s).
at room temperature, KGP-02 (50 g) and THF (300 ml) are added into a reaction bottle, 75g of methyl phosphonoacetate diethyl ester is added, 10g of sodium methoxide solid is added, the temperature of the system is kept below 40 ℃ after the addition, and the reaction is stirred until the reaction is completed, and can be completed within one hour. After the reaction is completed, 4v of water is added, the pH is regulated to 4 by a proper amount of hydrochloric acid, THF is removed under reduced pressure at 40 ℃, a proper amount of water is added after the removal, stirring, suction filtration and drying (50 ℃) are carried out, and the KGP-03 crude product is obtained, and the yield is 115%. FIGS. 3 and 4 show HNMR and CNMR patterns of KGP-03, respectively, as follows:
1 H NMR(400MHz,CDCl 3 )δ6.95(s,1H),5.55-6.04(m,2H),3.73(s,3H),2.33(m,5H),1.5-2.1(m,14H),1.18(m,6H),0.96(m,6H),0.72(s,3H).
13 C NMR(101MHz,CDCl 3 )δ199.52(s),171.42(s),166.97(s),148.31(s),123.80(s),122.23(s),55.77(s),55.52(s),57.32(s),51.37(s),42.48(s),39.43(s),38.99(s),38.57(s),35.68(s),35.61(s),35.60(s),33.91(s),32.89(s),31.98(s),28.16(s),24.14(s),20.98(s),18.92(s),17.37(s),11.96(s).
250ml of isopropenyl acetate was added to the clean and dry reaction flask. 0.5g PTS was added with stirring, and stirred for 5 minutes. A further 50g KGP-03 were added. Heating to 85 ℃ for reflux reaction for 3 hours, cooling to below 10 ℃ after the reaction is completed, slowly adding 1g of triethylamine, and concentrating to a small volume at 45 ℃ under reduced pressure. 100ml of methanol is added, the mixture is concentrated under reduced pressure until the mixture is thick, the temperature is reduced to 5 ℃ and the mixture is stirred for 1 hour. Suction filtering and drying at 55 deg.c to obtain KGP-04 in 103%. FIGS. 5 and 6 show HNMR and CNMR profiles of KGP-04, respectively, as follows:
1 H NMR(400MHz,CDCl 3 )δ6.96(s,1H),5.82(d,J＝15.6Hz,1H),5.69(s,1H),5.39(s,1H),3.73(s,3H),2.44(s,1H),2.29(s,1H),2.13(s,3H),2.07–1.04(m,19H),0.97(m,6H),0.72(s,3H).
13 C NMR(101MHz,CDCl 3 )δ169.38(s),167.02(s),148.50(s),147.00(s),139.39(s),123.95(s),122.16(s),116.98(s),56.73(s),55.58(s),51.36(s),47.91(s),42.55(s),39.56(s),39.07(s),35.66(s),34.89(s),33.77(s),31.82(s),31.75(s),28.23(s),24.81(s),24.17(s),21.16(s),21.09(s),18.99(s),18.83(s),11.98(s).
200ml of tetrahydrofuran, 200ml of methanol and 6.5g of sodium borohydride were weighed into a reaction flask under stirring, and then 3.5g of anhydrous lithium chloride was weighed into the reaction flask. Cooling to-5 ℃ under stirring. Then 50g KGP-04 is added, and the reaction is carried out for 8 hours at minus 5 ℃ after the addition. After the reaction is finished, the second reaction solution is slowly added into 500ml of water, glacial acetic acid is slowly added dropwise to adjust the pH to 4, the mixture is stirred for 2 hours, the mixture is filtered by suction, a filter cake is washed to be neutral by drinking water, a KGP-05 wet product is obtained by suction, and the KGP-05 wet product is obtained by drying, wherein the yield is 88.9%, and the purity is 96.5%. FIGS. 7, 8 and 9 show HNMR, CNMR and HPLC profiles of KGP-05, respectively, as follows:
1 H NMR(400MHz,CDCl 3 )δ6.96(s,1H),5.82(d,J＝15.6Hz,1H),5.35(s,1H),3.73(s,3H),3.52(s,1H),2.26(s,3H),1.96(s,3H),1.84(s,3H),1.74–1.07(m,14H),δ1.01(s,3H),0.95(m,3H),0.69(s,3H).
13 C NMR(101MHz,CDCl 3 )δ167.06(s),148.55(s),140.81(s),122.14(s),121.59(s),71.74(s),56.66(s),55.56(s),51.38(s),50.06(s),42.43(s),42.29(s),39.59(s),39.08(s),37.25(s),36.50(s),35.66(s),31.9(s),31.86(s),31.64(s),28.23(s),24.27(s),21.04(s),19.40(s),19.00(s),11.88(s).
200ml of dichloromethane and 200ml of methanol are added into a reaction bottle, 50g of KGP-05 and 0.5g of Raney nickel are added under stirring, nitrogen is replaced for 3 times, the temperature is reduced to 0 ℃, hydrogen is introduced into the system, and the reaction is kept at 0 ℃ for 8 hours. After the reaction is finished, stopping introducing hydrogen, turning off a gas cylinder, replacing nitrogen, carrying out suction filtration, carefully collecting a filter cake for later use, and carrying out suction drying to obtain a KGP-06 solution. Concentrating under reduced pressure at 40deg.C to obtain a thick solution, substituting 50ml of methanol to obtain a thick solution, cooling to about 5deg.C, and crystallizing for 0.5 hr. Suction filtration, leaching with a little methanol, drying the solid at 50 ℃ to obtain KGP-06 with the yield of 99%.
250ml of tetrahydrofuran and nitrogen are added into a clean and dry reaction bottle for replacement, 50g of KGP-06 solid is added for stirring, and the temperature is reduced to below 0 ℃ under the protection of nitrogen. The temperature of the reaction system is reduced to below 0 ℃, 120ml of methyl magnesium chloride solution (3M) is added dropwise, and the temperature of the system is controlled to below 15 ℃. After the reaction, 400ml of tap water and 50ml of concentrated hydrochloric acid are added into the beaker, and the mixture is stirred and cooled. The first reaction solution is slowly poured into acid water, and the internal temperature is controlled below 40 ℃. Concentrating under reduced pressure at a temperature below 50deg.C until no tetrahydrofuran exists, cooling, adding water, and measuring pH to 4. Cooling to below 30deg.C, suction filtering, and washing with water. After drying the solid, 250ml of DCM and 250ml of methanol are added for dissolution, the mixture is concentrated under reduced pressure at 40 ℃, the methanol is replaced to be thick, the temperature is reduced to about 5 ℃ for crystallization for 1h, the mixture is filtered, and the mixture is dried at 50 ℃ to obtain KOH-07 (25 hydroxy cholesterol) with the yield of 97% and the purity of 99.4%. FIGS. 10, 11 and 12 show HNMR, CNMR and HPLC profiles of KGP-07, respectively, as follows:
1 H NMR(400MHz,DMSO)δ5.26(s,1H),4.58(s,1H),4.02(s,1H),,2.27–0.78(m,40H),0.65(s,3H).
13 C NMR(101MHz,DMSO)δ141.74(s),120.88(s).,70.48(s),69.23(s),56.70(s),56.11(s),50.11(s),42.34(s),40.64(s),40.43(s),40.23(s),40.02(s),39.81(s),39.39(s),36.54(s),31.96(s),29.89(s),29.71(s),19.62(s),19.04(s),12.14(s)(with 6 carbon letters Number peak overlaps with other signal peaks).
Example 2
The embodiment provides a preparation method of 25-hydroxycholesterol, which comprises the following steps:
100g of (methoxymethyl) triphenyl phosphorus chloride and 300ml of DMSO are added into a reaction bottle, 12.5g of 60% NaH is added under stirring, the system temperature is kept to be less than 30 ℃, stirring is carried out for 1h after the addition is finished, then 60g of KGP-01 is added for reaction, the system temperature is kept to be not higher than 40 ℃, and TLC monitoring reaction is carried out. Developing agent: PE: ea=4:1. After the reaction was completed, 4v water was added to quench, hydrochloric acid was added to adjust pH to 5, the aqueous layer was extracted with dichloro, the organic phases were combined, and the solvent was concentrated under reduced pressure at 40℃to give an oil. Adding 250 acetone into the oily matter, heating to 40 ℃, slowly dripping 350ml of water, cooling to 10 ℃ after dripping water, stirring for 30min, carrying out suction filtration, washing with water, and drying (50 ℃) to obtain KGP-02 fine product, wherein the yield is more than 98.2%.
At room temperature, KGP-02 (50 g) and THF (300 ml) are added into a reaction bottle, 75g of methyl phosphonoacetate diethyl ester is added, 10g of sodium methoxide solid is added, the temperature of the system is kept below 40 ℃ after the addition, and the reaction is stirred until the reaction is completed, and can be completed within one hour. After the reaction is completed, 4v of water is added, the PH is regulated to 5 by a proper amount of hydrochloric acid, THF is removed under reduced pressure at 40 ℃, a proper amount of water is added after the removal, stirring, suction filtration and drying (50 ℃) are carried out, and the KGP-03 crude product is obtained, and the yield is 110%.
250ml of isopropenyl acetate was added to the clean and dry reaction flask. 0.5g PTS was added with stirring, and stirred for 5 minutes. A further 50g KGP-03 were added. Heating to 80 ℃ for reflux reaction for 3 hours, cooling to below 10 ℃ after the reaction is completed, slowly adding 1g of triethylamine, and concentrating to a small volume at 45 ℃ under reduced pressure. 100ml of methanol is added, the mixture is concentrated under reduced pressure until the mixture is thick, the temperature is reduced to 5 ℃ and the mixture is stirred for 1 hour. Suction filtering and drying at 50 ℃ to obtain KGP-04 with 104 percent of yield.
200ml of tetrahydrofuran, 200ml of methanol and 0.13g of sodium borohydride were weighed into a reaction flask under stirring, and then 3.5g of anhydrous lithium chloride was weighed into the reaction flask. Cooling to-5 ℃ under stirring. Then 50g KGP-04 is added, and the reaction is carried out for 8 hours at minus 5 ℃ after the addition. After the reaction is finished, the second reaction solution is slowly added into 500ml of water, glacial acetic acid is slowly added dropwise to adjust the pH to 5, the mixture is stirred for 2 hours, suction filtration is carried out, a filter cake is washed to be neutral by drinking water, a KGP-05 wet product is obtained after suction drying, and the KGP-05 is obtained after drying, wherein the yield is 88.3%, and the purity is 94.7%.
200ml of dichloromethane and 200ml of methanol are added into a reaction bottle, 50g of KGP-05 and 1g of Raney nickel are added under stirring, nitrogen is replaced for 3 times, the temperature is reduced to 0 ℃, hydrogen is introduced into the system, and the reaction is kept at 0 ℃ for 8 hours. After the reaction is finished, stopping introducing hydrogen, turning off a gas cylinder, replacing nitrogen, carrying out suction filtration, carefully collecting a filter cake for later use, and carrying out suction drying to obtain a KGP-06 solution. Concentrating under reduced pressure at 40deg.C to obtain a thick solution, substituting 50ml of methanol to obtain a thick solution, cooling to about 5deg.C, and crystallizing for 0.5 hr. Suction filtration, leaching with a little methanol, drying the solid at 50 ℃ to obtain KGP-06 with the yield of 98.5%.
250ml of tetrahydrofuran and nitrogen are added into a clean and dry reaction bottle for replacement, 50g of KGP-06 solid is added for stirring, and the temperature is reduced to below 0 ℃ under the protection of nitrogen. The temperature of the reaction system is reduced to below 0 ℃, 130ml of methyl magnesium chloride solution (2.5M) is added dropwise, and the temperature of the system is controlled to below 15 ℃. After the reaction, 400ml of tap water and 50ml of concentrated hydrochloric acid are added into the beaker, and the mixture is stirred and cooled. The first reaction solution is slowly poured into acid water, and the internal temperature is controlled below 40 ℃. Concentrating under reduced pressure at a temperature below 50deg.C until no tetrahydrofuran exists, cooling, adding water, and measuring pH to 3. Cooling to below 30deg.C, suction filtering, and washing with water. After drying the solid, 250ml of DCM and 250ml of methanol are added for dissolution, the mixture is concentrated under reduced pressure at 40 ℃, the methanol is replaced to be thick, the temperature is reduced to about 5 ℃ for crystallization for 1h, the mixture is filtered, and the mixture is dried at 50 ℃ to obtain KOH-07 (25 hydroxy cholesterol) with the yield of 96.4% and the purity of 98.3%.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.
Claims (10)
1. A method for preparing 25-hydroxycholesterol, comprising the steps of:
tetrahydrofuran and KGP-06 are mixed and cooled to below 0 ℃ under the protection of nitrogen, and then methyl magnesium chloride solution is added dropwise, and the reaction temperature is controlled below 15 ℃; after the reaction is completed, continuously adding hydrochloric acid solution to obtain a first reaction solution;
pouring the first reaction liquid into acid water, controlling the temperature below 40 ℃, concentrating, adding water, cooling to below 30 ℃, carrying out suction filtration, washing with water, drying to obtain a solid, adding DCM and methanol to dissolve the solid, concentrating, adding methanol to replace to be thick, and cooling and crystallizing to obtain the 25-hydroxy cholesterol;
the KGP-06 has the structural formula:
2. the method for preparing 25-hydroxycholesterol according to claim 1, wherein the dosage ratio of KGP-06 to methyl magnesium chloride solution is 50g (120-130) mL, and the concentration of methyl magnesium chloride solution is 2.5-3mol/L.
3. The process for preparing 25-hydroxycholesterol according to claim 1, wherein KGP-06 is prepared by the steps of:
mixing dichloromethane and methanol, adding KGP-05 and Raney nickel, introducing nitrogen for replacement, cooling to 0-5 ℃, and continuously introducing hydrogen for reaction to obtain KGP-06;
the KGP-05 has the structural formula:
4. the method for preparing 25-hydroxy cholesterol according to claim 3, wherein the mass ratio of KGP-05 to Raney nickel is 100 (1-2).
5. A process for the preparation of 25 hydroxy cholesterol according to claim 3, wherein KGP-05 is prepared by the steps of:
mixing tetrahydrofuran, methanol and sodium borohydride, adding anhydrous lithium chloride, cooling to-5-0 ℃ under the stirring action, adding KGP-04 for continuous reaction, obtaining a second reaction liquid after the reaction is completed, slowly adding the second reaction liquid into water, then dropwise adding glacial acetic acid to adjust the pH to 4-5, and stirring to obtain KGP-05; the KGP-04 has the structural formula:
6. the method for preparing 25-hydroxycholesterol according to claim 5, wherein the KGP-04 is prepared by the steps of: adding PTS into isopropenyl acetate under the stirring action, continuously adding KGP-03, heating to 80-85 ℃ for reflux reaction, cooling to below 10 ℃ after the reaction is completed, continuously adding triethylamine, concentrating at 45-50 ℃, adding methanol, continuously concentrating until the material is thick, cooling to 5-10 ℃ and continuously stirring to obtain KGP-04;
the KGP-03 has the structural formula:
7. the method for producing 25-hydroxycholesterol according to claim 6, wherein the time for the reflux reaction is 3 to 4 hours.
8. The method for preparing 25-hydroxycholesterol according to claim 6, wherein the KGP-03 is prepared by the steps of:
mixing KGP-02 with THF, adding methyl phosphonoacetate diethyl ester, adding sodium methoxide, keeping the temperature below 40 ℃ for stirring reaction until the reaction is complete, and adding water and hydrochloric acid to adjust the pH to 4-5 to obtain KGP-03;
the KGP-02 has the structural formula:
9. the method for preparing 25-hydroxycholesterol according to claim 8, wherein the KGP-02 is prepared by the steps of:
mixing (methoxymethyl) triphenyl phosphorus chloride and DMSO, adding NaH, reacting at a temperature of less than 30 ℃, adding KGP-01, performing TLC monitoring reaction at a temperature of less than 40 ℃, adding water, adding hydrochloric acid to adjust pH to 4-5, extracting a water layer with dichloro, combining organic phases, concentrating to obtain oily matter, adding acetone into the oily matter, heating to 40-45 ℃, adding water dropwise, cooling to 5-10 ℃, and stirring to obtain KGP-02;
the structural formula of the KGP-01 is as follows:
10. the method for preparing 25-hydroxycholesterol according to claim 9, wherein the mass ratio of (methoxymethyl) triphenylphosphine chloride to KGP-01 is 10 (5-6).
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