CN114276284A - Preparation method of fluocalcitol - Google Patents
Preparation method of fluocalcitol Download PDFInfo
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- CN114276284A CN114276284A CN202111654227.4A CN202111654227A CN114276284A CN 114276284 A CN114276284 A CN 114276284A CN 202111654227 A CN202111654227 A CN 202111654227A CN 114276284 A CN114276284 A CN 114276284A
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Abstract
The invention belongs to the field of organic chemistry, and discloses a method for preparing fluorcalciferol by adopting a convergent synthesis route, which comprises the following steps: reacting the compound 1 with an oxidant in an organic solvent I to obtain a compound 3; reacting the compound 3 with a hydroxyl protecting group reagent containing silicon base in an organic solvent II under an alkaline condition to obtain a compound 4; carrying out coupling reaction on the compound 4 and the compound 2 in an organic solvent III under an alkaline condition to obtain a compound 5; and reacting the compound 5 with a desiliconized protecting group reagent in an organic solvent IV to obtain the fluorcalciferol. The invention has the advantages that: compared with the traditional synthetic route, the convergent synthetic route is adopted for preparing the fluocalcitol for the first time, and the method has the advantages of short synthetic route, less by-products, simplicity in purification, high yield and suitability for industrial production, avoids the use of virulent reagents MOMCl and methanesulfonic acid, is environment-friendly, improves the yield, and improves the total yield to over 70%.
Description
Technical Field
The invention belongs to the field of organic chemistry, and relates to a preparation method of fluorcalciferol.
Technical Field
Fluecalcitol (Falecalcitol), a calcitriol analogue developed by the union of Dainippon (Taisho), Kissei and Dainippon Sumitomo, has high potency in vivo and in vitro and a longer duration of action in vivo. The composition can improve bone diseases and symptoms caused by vitamin D deficiency, and promote absorption to supplement deficient calcium and prevent osteoporosis. Can be used for treating secondary hyperparathyroidism, hypoparathyroidism, rickets and osteomalacia of patients during dialysis.
Literature reports that the conventional synthetic route for the fluorocalcitol uses cholesterol or vitamin D2 and derivatives thereof as starting materials and is subjected to multi-step conversion to prepare the fluorocalcitol:
(1) patent US358406 discloses a method for preparing a fluorocalciferol, which uses a cholesterol compound as a starting material, involves complex operations such as oxidation, reduction ring opening, illumination ring opening and the like, generates a large amount of by-products, causes great difficulty in purification, and has a total yield of only 1.38% in a route. The synthetic route is as follows (formula 2):
(2) patent US6080879 discloses a method for preparing fluorcalciferol, which uses vitamin D2 derivative as starting material, and relates to operations such as oxidation, reduction, ring opening and overturning, and uses virulent reagents such as selenium dioxide and hexafluoroacetone in the reaction process, and the fluorcalciferol is obtained through 12 steps of reaction, so that the industrial production difficulty is extremely high due to the overlong route, and the total yield is only 3.96%. The synthetic route is as follows (formula 3):
the synthesis method integrates the problems of long route, complex operation, low yield and unsuitability for industrial production of the traditional fluocalciferol synthesis route.
Attempts to prepare the fluorocalciferol by using a convergent synthesis route have been the focus of research, and in order to prepare the fluorocalciferol CD ring intermediates used in the convergent synthesis route, patents CN111960938A and CN112047820A report two synthetic methods for the fluorocalciferol CD ring intermediates, the structural formula of which is as follows:
the tertiary hydroxyl of the side chain of the intermediate of the fluorocalcitol CD ring is protected by methoxy methyl ether (MOM), a virulent reagent chloromethyl methyl ether (MOMCl) is required to be used, and a virulent methane sulfonic acid reagent is also required to be used for deprotection reaction. Therefore, the fluorcalciferol CD ring intermediate is not suitable for being used as a material for preparing the fluorcalciferol by a convergent synthetic route.
Disclosure of Invention
Aiming at the problems existing in the traditional synthetic route of the fluocalciferol and the preparation of a fluocalciferol CD ring intermediate. The invention adopts a convergent synthesis route to prepare the fluorcalciferol for the first time, and solves the problems of long reaction route, complex operation, low yield and unsuitability for industrial production in the traditional synthesis route. The tertiary hydroxyl of the side chain of the fluorinated calciferol CD ring is protected by using a hydroxyl protecting group reagent containing silicon, so that the use of a virulent reagent MOMCl (upper protection) and methanesulfonic acid (deprotection) is avoided, the generation of byproducts is reduced, and the yield is improved. The technical scheme is as follows (formula 1):
step one, reacting the compound 1 with an oxidant in an organic solvent I to obtain a compound 3.
Dissolving the compound 1 in an organic solvent I, adding an oxidant, stirring and reacting for 3-6 h at 25-30 ℃, and filtering, purifying and the like to obtain a compound 3;
in the first step, the oxidant is one or more of pyridinium dichlorochromate, pyridinium chlorochromate, chromium trioxide, sulfur trioxide pyridine and Pyridinium Dichromate (PDC), more preferably PDC, and the molar charge ratio is 1.5-5 times, preferably 2.5 times of that of the compound 1; the organic solvent may be one or more of dichloromethane, chloroform, n-heptane, acetone, isopropyl acetate, Tetrahydrofuran (THF), and dimethyl sulfoxide, preferably dichloromethane.
Step two: and reacting the compound 3 with a silane protecting group reagent in an organic solvent II under the alkaline condition to obtain a compound 4.
Dissolving the compound 3 in an organic solvent II, adding an organic base reagent, cooling to 0-10 ℃ under the protection of nitrogen, slowly adding a silane protecting group reagent or a solution of the silane protecting group solvent II, reacting at 20-50 ℃ for 8-36h, diluting with the solvent II after the reaction is finished, washing with 2% hydrochloric acid and a saturated sodium bicarbonate aqueous solution, washing with water in sequence, and purifying to obtain a compound 4.
In step two, when the protecting group R1In the case of Trimethylsilyl (TMS), the silane protecting group reagent can be trimethylchlorosilane (TMSCl) or trimethylsilyl trifluoromethanesulfonate (TMSOTf), preferably TMSCl, and the molar charge ratio is 1.1-20 times, preferably 6 times that of the compound 3; the organic base is one or more of triethylamine, Diisopropylethylamine (DIPEA), pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, 1, 8-diazabicycloundecen-7-ene (DBU), sodium hydride (NaH) and 4-Dimethylaminopyridine (DMAP), preferably imidazole, and the molar charge ratio is 1.2-30 times, preferably 9 times of that of the compound 3; the organic solvent II can be one or more of chloroform, dichloromethane, dichloroethane, N-Dimethylformamide (DMF), THF, acetonitrile, dioxane and toluene, and dichloromethane is preferred; the reaction temperature is excellentSelecting the temperature of 25-30 ℃.
In step two, when the protecting group R1In the case of Triethylsilyl (TES), the silane protecting group reagent can be triethylchlorosilane (TESCl) or triethylsilyl trifluoromethanesulfonate (TESOTf), preferably TESCl, and the molar charge ratio is 1.1-20 times, preferably 4 times that of the compound 3; the organic base is one or more of triethylamine, DIPEA, pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, DBU, NaH and DMAP, preferably triethylamine, and the molar charge ratio is 1.2-30 times, preferably 6 times of that of the compound 3; the organic solvent II can be one or more of chloroform, dichloromethane, dichloroethane, DMF, THF, acetonitrile, dioxane and toluene, and dichloromethane is preferred; the reaction temperature is preferably 25-30 ℃.
In step two, when the protecting group R1When the compound is tert-butyldimethylsilyl (TBDMS), the silane protecting group reagent can be tert-butyldimethylsilyl chloride (TBDMSCl) or tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), preferably TBDMSCl, and the molar charge ratio is 1.1-20 times, preferably 4 times of that of the compound 3; the organic base is one or more of triethylamine, DIPEA, pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, DBU, NaH and DMAP, preferably triethylamine, and the molar charge ratio is 1.2-30 times, preferably 6 times of that of the compound 3; the organic solvent II can be one or more of chloroform, dichloromethane, dichloroethane, DMF, THF, acetonitrile, dioxane and toluene, and dichloromethane is preferred; the reaction temperature is preferably 35-40 ℃.
In step two, when the protecting group R1When the compound is tert-butyl diphenyl silicon base (TBDPS), the silane protecting group reagent can be tert-butyl diphenyl chlorosilane (TBDPSCl) or tert-butyl diphenyl silicon triflate (TBDPSOTf), preferably TBDPSOTf, and the molar charge ratio is 1.1-20 times, preferably 6 times of that of the compound 3; the organic base is one or more of triethylamine, DIPEA, pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, DBU, NaH and DMAP, preferably DIPEA, and the molar charge ratio is 1.2-30 times, preferably 9 times of that of the compound 3; the organic solvent II can be one or more of chloroform, dichloromethane, dichloroethane, DMF, THF, acetonitrile, dioxane and tolueneSeed, preferably dichloromethane; the reaction temperature is preferably 35-40 ℃.
In step two, when the protecting group R1In the case of triisopropyl silicon base (TIPS), the silane protecting group reagent can be triisopropyl chlorosilane (TIPSCl) or triisopropyl silyl trifluoromethanesulfonate (TIPSOTf), preferably TIPSOTf, and the molar charge ratio is 1.1-20 times, preferably 6 times of that of the compound 3; the organic base is one or more of triethylamine, DIPEA, pyridine, 2, 6-lutidine, 2,4, 6-collidine, imidazole, DBU, NaH and DMAP, preferably 2, 6-lutidine, and the molar charge ratio is 1.2-30 times, preferably 9 times of that of the compound 3; the organic solvent II can be one or more of chloroform, dichloromethane, dichloroethane, DMF, THF, acetonitrile, dioxane and toluene, and dichloromethane is preferred; the reaction temperature is preferably 35-40 ℃.
In step two, a silane protecting group R1More preferably TES.
Step three: and (3) carrying out coupling reaction on the compound 4 and the compound 2 in an organic solvent III under an alkaline condition to obtain a compound 5.
Dissolving the compound 2 in a solvent III under the protection of nitrogen, cooling to-80 to-40 ℃, adding an organic metal alkali reagent, adding a solvent III solution of the compound 4, reacting for 2 hours at-80 to-40 ℃, quenching by a saturated ammonium chloride solution, extracting by Ethyl Acetate (EA), washing by water, drying, and purifying to obtain a compound 5.
In the third step, the molar ratio of the compound 4, the compound 2 and the alkali is 1 (1.1-2) to 1.1-3, preferably 1:1.5: 3; wherein the base can be n-butyllithium, t-butyllithium, isobutyllithium, sec-butyllithium, methyllithium, ethyllithium, propyllithium, phenyllithium, etc., preferably n-butyllithium; the organic solvent III can be one or more of anhydrous THF, anhydrous diethyl ether, anhydrous dimethyl ether, anhydrous hexane and anhydrous heptane, and anhydrous THF is preferred; the reaction temperature is-80 ℃ to-40 ℃, preferably-75 ℃ to-70 ℃.
Step four: deprotection of compound 5 in organic solvent four under acidic conditions or under conditions of a fluoride ion-containing reagent affords compound 6.
Dissolving the compound 5 in an organic solvent IV, adding acid or an acid water solution or a fluorine-containing ion reagent, stirring for 12-36 h at 25-60 ℃, and performing post-treatment, purification and other operations to obtain the compound 6-fluorocalcitol.
In the fourth step, the deprotection reaction can be performed in the presence of acids such as sulfuric acid, hydrofluoric acid, hydrochloric acid and the like, or in the presence of fluorine-containing ionic reagents such as tetrabutylammonium fluoride (TBAF), tetraethylammonium fluoride, tetramethylammonium fluoride, cesium fluoride and the like, preferably TBAF, and the molar charge ratio is 5-50 times, preferably 15 times, of that of the compound 5; the organic solvent II can be one or more of methanol, ethanol, THF, acetonitrile, dichloromethane and EA, preferably THF, and the reaction temperature is 10-55 ℃, preferably 25-30 ℃.
The invention has the advantages that: the convergent synthesis route is adopted for preparing the fluocalcitol for the first time, and compared with the traditional synthesis route, the method has the advantages of short synthesis route, less by-products, simplicity in purification, high yield and suitability for industrial production. In addition, the invention uses a silicon-based hydroxyl protecting group reagent to protect the tertiary hydroxyl of the side chain of the fluorinated calciferol CD ring, avoids the use of MOMCl for upper protection and a methane sulfonic acid highly toxic reagent for deprotection, is environment-friendly, improves the yield, and improves the total yield to more than 70 percent.
Drawings
FIG. 1 is a route for the preparation of fluorochalcol
FIG. 2 shows Compound 4 (R)1TES) nuclear magnetic hydrogen spectrum;
FIG. 3 shows Compound 5 (R)1TES) nuclear magnetic hydrogen spectrum;
FIG. 4 is a nuclear magnetic hydrogen spectrum of Compound 6 (Flucalcitol).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Referring to fig. 1, a reaction scheme of a method for preparing a fluorocalciferol, comprising the steps of:
the method comprises the following steps: reacting the compound 1 with an oxidant in an organic solvent I to obtain a compound 3;
step two: reacting the compound 3 with a silicon-based protecting group reagent in an organic solvent II under an alkaline condition to obtain a compound 4;
step three: carrying out coupling reaction on the compound 4 and the compound 2 in an organic solvent III under an alkaline condition to obtain a compound 5;
step four: deprotecting compound 5 in organic solvent IV with an acidic reagent or a fluorine-containing ion reagent to obtain compound 6: flucalcitol
In the first step, the oxidant is one or more of pyridinium dichlorochromate, pyridinium chlorochromate, chromium trioxide, sulfur trioxide pyridine and pyridinium dichromate, and the molar charge amount of the oxidant is 1.5-5 times of that of the compound 1; the organic solvent I is one or more of dichloromethane, chloroform, n-heptane, acetone, isopropyl acetate, tetrahydrofuran and dimethyl sulfoxide; the reaction temperature is 15-45 ℃.
In addition to the above examples, R in Compound 41Is a silane protecting group.
Preferably, the silane protecting group is one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.
In the second step, the silicon-containing hydroxyl protecting group reagent is one of trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, triethylchlorosilane, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylchlorosilane, tert-butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylchlorosilane, tert-butyldiphenylsilyl trifluoromethanesulfonate, triisopropylchlorosilane and triisopropylsilyl trifluoromethanesulfonate.
In the second step, the molar ratio of the compound 3, the hydroxyl protecting group reagent containing the silicon base and the base is 1 (1.1-20) to 1.2-30, wherein the base is one or more of triethylamine, diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, 1, 8-diazabicycloundecen-7-ene, sodium hydride and 4-dimethylaminopyridine; the organic solvent II is one or more of chloroform, dichloromethane, dichloroethane, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane and toluene; the reaction temperature is 10-50 ℃.
In the third step, the molar ratio of the compound 4 to the compound 2 to the alkali is 1 (1.1-2) to 1.1-4; wherein the base is one of n-butyllithium, tert-butyllithium, isobutyllithium, sec-butyllithium, methyllithium, ethyllithium, propyllithium and phenyllithium; the organic solvent III is one or more of anhydrous tetrahydrofuran, anhydrous ether, anhydrous dimethyl ether, anhydrous hexane and anhydrous heptane, and the reaction temperature is-80 to-40 ℃.
The acidic reagent is sulfuric acid, hydrofluoric acid or hydrochloric acid; the fluorine-containing ion reagent is tetrabutylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium fluoride and cesium fluoride; wherein the molar inventory rating of the acid reagent or the fluorine-containing ion reagent is 5-30 times of that of the compound 5; the organic solvent IV is one or more of methanol, ethanol, THF, acetonitrile, dichloromethane and ethyl acetate; the reaction temperature is 10-55 ℃.
Example 1: preparation of Compound 3
Compound 1(10g, 25.6mmol) and dichloromethane (200mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, the mixture was dissolved with stirring, PDC (24.1g, 64.0mmol) was added to turn the system dark brown, the reaction was carried out at 25 to 30 ℃ for 3 hours, and the starting material was monitored by TLC (developing solvent: PE/EA ═ 2:1) and reacted completely. Filtering the reaction solution, assisting filtration with diatomite, leaching filter residues with dichloromethane, concentrating the filtrate under reduced pressure, purifying by column chromatography, and eluting with an eluent: n-hexane/EA ═ 10:1 → 5:1, vacuum dried at 25-30 ℃ for 30min to give 9.45g of white granular solid with a yield of 95%.
Example 2: compound 4 (R)1TMS) preparation
Compound 3(1.0g, 2.57mmol), imidazole (1.57g, 23.13mmol) and dichloromethane (20mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, stirred to dissolve, cooled to 0 ℃, TMSCl (2.3g, 15.42mmol) was added dropwise, after the addition, the temperature was raised to 25-30 ℃ for reaction for 12h, and TLC monitoring (developing agent: PE: EA ═ 5:1) was performed to substantially complete the reaction of the starting materials. The reaction mixture was diluted with dichloromethane (100mL), washed with a 2% aqueous hydrochloric acid solution (50mL), a saturated aqueous sodium bicarbonate solution (50mL), and purified water (50mL × 2) in this order, the organic phase was dried over anhydrous magnesium sulfate, the filtrate was concentrated, and purified with a silica gel column, eluent: n-hexane/EA 50:1 → 20:1, vacuum drying at 25-30 ℃ to give 1.04g of a colorless transparent oily product with a yield of 88%.
Example 3: compound 4 (R)1TES) preparation
Compound 3(1.0g, 2.57mmol), triethylamine (1.56g, 15.42mmol) and dichloromethane (20mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, the mixture was stirred and dissolved, cooled to 0 ℃, TESCl (1.55g, 10.28mmol) was added dropwise, after the addition, the temperature was raised to 25 to 30 ℃ for reaction for 8 hours, and TLC monitoring (developing agent: PE: EA ═ 5:1) was performed to complete the reaction of the starting materials. The reaction mixture was diluted with dichloromethane (100mL), washed with a 2% aqueous hydrochloric acid solution (50mL), a saturated aqueous sodium bicarbonate solution (50mL), and purified water (50mL × 2) in this order, and the organic phase was dried over anhydrous magnesium sulfate, purified with a silica gel column, and eluted with: n-hexane/EA 50:1 → 20:1, vacuum drying at 25-30 ℃ to give 1.2g of a colorless transparent oily product with a yield of 95%.
FIG. 2 shows Compound 4 (R)1TES), the results are as follows:
1H NMR(CDCl3):δ(ppm):2.47(dd,H),2.28(m,H),2.26(m,H),2.13(m,H),2.02(m,H),1.93～1.84(m,3H),1.77～1.71(m,2H),1.62～1.51(m,3H),1.47～1.29(m,5H),1.09～1.07(m,H),0.98～0.96(t,9H),0.95(s,3H),0.70～0.66(q,6H),0.65(s,3H).
example 4: compound 4 (R)1TBDMS) preparation
Compound 3(1.0g, 2.57mmol), triethylamine (1.56g, 15.42mmol) and dichloromethane (20mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, the mixture was stirred and dissolved, the temperature was reduced to 0 ℃, a solution of TBDMSCl (1.55g, 10.28mmol) in dichloromethane (5mL) was added dropwise, after the addition, the temperature was raised to 35 ℃ for reaction for 24 hours, and the starting material was monitored by TLC (developing reagent: PE: EA ═ 5:1) for substantial completion of the reaction. The reaction mixture was diluted with dichloromethane (100mL), washed with a 2% aqueous hydrochloric acid solution (50mL), a saturated aqueous sodium bicarbonate solution (50mL), and purified water (50mL × 2) in this order, the organic phase was dried over anhydrous magnesium sulfate, the filtrate was concentrated, and purified with a silica gel column, eluent: n-hexane/EA ═ 50:1 → 20:1, vacuum drying at 25-30 ℃ gave 1.09g of a colorless transparent oily product in 84% yield.
Example 5: compound 4 (R)1TBDPS) preparation
Compound 3(1.0g, 2.57mmol), DIPEA (3.0g, 23.13mmol) and dichloromethane (20mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, the mixture was stirred and dissolved, the temperature was reduced to 0 ℃, a solution of TBDPSOTf (6.0g, 15.42mmol) in dichloromethane (5mL) was added dropwise, after the addition, the temperature was raised to 35 ℃ for reaction for 36 hours, and the starting material was monitored by TLC (developing reagent: PE: EA ═ 5:1) for substantial completion of the reaction. The reaction mixture was diluted with dichloromethane (100mL), washed with a 2% aqueous hydrochloric acid solution (50mL), a saturated aqueous sodium bicarbonate solution (50mL), and purified water (50mL × 2) in this order, and the organic phase was dried over anhydrous magnesium sulfate, purified with a silica gel column, and eluted with: n-hexane/EA 50:1 → 20:1, vacuum drying at 25-30 ℃ to give 1.32g of a colorless transparent oily product in a yield of 82%.
Example 6: compound 4 (R)1TIPS) preparation
Compound 3(1.0g, 2.57mmol), 2, 6-lutidine (2.5g, 23.13mmol) and dichloromethane (20mL) were added to a nitrogen-protected three-necked reaction flask at room temperature, the mixture was stirred and dissolved, the temperature was reduced to 0 ℃, a solution of tipstotf (4.7g, 15.42mmol) in dichloromethane (5mL) was added dropwise, after the completion of the addition, the temperature was raised to 35 ℃ for reaction for 36 hours, and the starting material was almost completely reacted by TLC monitoring (developing agent: PE: EA: 5: 1). The reaction mixture was diluted with dichloromethane (100mL), washed with a 2% aqueous hydrochloric acid solution (50mL), a saturated aqueous sodium bicarbonate solution (50mL), and purified water (50mL × 2) in this order, and the organic phase was dried over anhydrous magnesium sulfate, purified with a silica gel column, and eluted with: n-hexane/EA 50:1 → 20:1, vacuum drying at 25-30 ℃ to give 1.36g of a colorless transparent oily product with a yield of 90%.
Example 7: compound 5 (R)1TES) preparation
Dissolving compound 2(1.74g, 2.98mmol) in anhydrous THF (17mL) under the protection of nitrogen, cooling to-75-70 ℃, dropwise adding a 1.6M hexane solution (3.7mL, 5.96mmol) of n-butyllithium to obtain a dark red system, dropwise adding a solution of compound 4(1.0g, 1.99mmol) in anhydrous THF (10mL), stirring at-75 ℃ for 1h after dropwise adding, monitoring by TLC (developing agent: PE: EA: 5:1) that compound 4 basically reacts, adding a saturated ammonium chloride solution (20mL) to quench the reaction, heating to room temperature, EA (40mL × 3) extracting, combining organic phases, washing with water (50mL × 3), drying anhydrous magnesium sulfate, purifying, eluting with silica gel column: n-hexane/EA ═ 80:1 → 50:1, vacuum drying at 25-30 ℃ gave 1.52g of a colorless transparent gel product in 88% yield.
FIG. 3 shows Compound 5 (R)1TES), the results are as follows:
1H NMR(CDCl3):δ(ppm):6.19(d,H),5.97(d,H),5.12(d,H),4.81(d,H),4.32(q,H),4.14(m,H),2.78(dd,H),2.40(dd,H),2.18(q,H),1.93(m,2H),1.81～1.78(m,3H),1.72～1.70(m,2H),1.61～1.60(m,2H),1.52～1.50(m,2H),1.43～1.41(m,2H),1.33～1.30(m,2H),1.24～1.20(m,4H),0.99(m,H),0.92～0.89(t,9H),0.89～0.87(d,3H),0.82(s,18H),0.64～0.60(q,6H),0.48(s,3H),0.02(d,6H),0.01(s,6H).
example 8: preparation of Compound 6 (Flucalcitol)
Adding compound 5(1.0g, 1.15mmol) and THF (10mL) into a reaction flask protected by nitrogen at room temperature, dropwise adding a THF solution (1M, 17.25mL, 17.25mmol) of TBAF, stirring at 20-25 ℃ in the dark for reaction for 5h after the dropwise adding is finished, monitoring by TLC (developing agent: dichloromethane/methanol ═ 10:1) to complete the reaction, adding EA (50mL) to dilute the reaction solution, washing with water (50 mL. times.3), washing with a saturated sodium chloride solution (50mL), drying with anhydrous magnesium sulfate, concentrating the filtrate, purifying by column chromatography, eluting with an eluent: dichloromethane/methanol 20:1, vacuum dried at 25-30 ℃ to give 0.52g of white powdery solid in 89% yield.
FIG. 4 is a nuclear magnetic hydrogen spectrum of Compound 6 (Flucalcitol), with the following results:
1H NMR(CDCl3):δ(ppm):6.39(d,H),6.03(d,H),5.33(s,H),5.00(s,H),4.44(m,H),4.24(m,H),2.84～2.81(dd,H),2.61～2.58(dd,H),2.33～2.31(m,H),2.01(m,3H),1.94～1.84(m,4H),1.69～1.62(m,6H),1.49～1.39(m,6H),1.31～1.25(m,4H),0.95(d,3H),0.55(s,3H)。
Claims (8)
1. a method for preparing a fluorochecalcitol, characterized in that it comprises the following steps:
the method comprises the following steps: reacting the compound 1 with an oxidant in an organic solvent I to obtain a compound 3;
step two: reacting the compound 3 with a silicon-based protecting group reagent in an organic solvent II under an alkaline condition to obtain a compound 4;
step three: carrying out coupling reaction on the compound 4 and the compound 2 in an organic solvent III under an alkaline condition to obtain a compound 5;
step four: deprotecting compound 5 in organic solvent IV with an acidic reagent or a fluorine-containing ion reagent to obtain compound 6: flucalcitol
2. The method for preparing the fluorocalciferol according to claim 1, wherein in the first step, the oxidant is one or more of pyridinium dichlorochromate, pyridinium chlorochromate, chromium trioxide, pyridine trioxide and pyridinium dichromate, and the molar charge amount of the oxidant is 1.5-5 times that of the compound 1; the organic solvent I is one or more of dichloromethane, chloroform, n-heptane, acetone, isopropyl acetate, tetrahydrofuran and dimethyl sulfoxide; the reaction temperature is 15-45 ℃.
3. The process according to claim 1, wherein R in Compound 4 is1Is a silane protecting group.
4. The method of claim 3, wherein the silane protecting group is one of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and triisopropylsilyl.
5. The method for preparing a fluorocalciferol as claimed in claim 1, wherein in the second step, the silicon group-containing hydroxyl protecting group reagent is one of trimethylchlorosilane, trimethylsilyltriflate, triethylchlorosilane, triethylsilyltriflate, t-butyldimethylchlorosilane, t-butyldimethylsilyltriflate, t-butyldiphenylchlorosilane, t-butyldiphenylsilyltriflate, triisopropylchlorosilane, and triisopropylsilyltriflate.
6. The method for preparing fluorocalcitol according to claim 1, wherein in the second step, the molar ratio of the compound 3, the hydroxyl protecting group reagent containing a silicon group and the base is 1 (1.1-20) to (1.2-30), wherein the base is one or more of triethylamine, diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, imidazole, 1, 8-diazabicycloundec-7-ene, sodium hydride and 4-dimethylaminopyridine; the organic solvent II is one or more of chloroform, dichloromethane, dichloroethane, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane and toluene; the reaction temperature is 10-50 ℃.
7. The method for preparing fluorocalcitol according to claim 1, wherein in the third step, the molar ratio of compound 4 to compound 2 to the base is 1 (1.1-2) to (1.1-4); wherein the base is one of n-butyllithium, tert-butyllithium, isobutyllithium, sec-butyllithium, methyllithium, ethyllithium, propyllithium and phenyllithium; the organic solvent III is one or more of anhydrous tetrahydrofuran, anhydrous ether, anhydrous dimethyl ether, anhydrous hexane and anhydrous heptane, and the reaction temperature is-80 to-40 ℃.
8. The process for the preparation of fluorocalciferol according to claim 1, wherein in the fourth step, the acidic agent is sulfuric acid, hydrofluoric acid or hydrochloric acid; the fluorine-containing ion reagent is tetrabutylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium fluoride and cesium fluoride; wherein the molar inventory rating of the acid reagent or the fluorine-containing ion reagent is 5-30 times of that of the compound 5; the organic solvent IV is one or more of methanol, ethanol, THF, acetonitrile, dichloromethane and ethyl acetate; the reaction temperature is 10-55 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114656384A (en) * | 2022-04-20 | 2022-06-24 | 正大制药（青岛）有限公司 | Preparation method of eldecalcitol 20S isomer |
| CN116354790A (en) * | 2023-02-14 | 2023-06-30 | 正大制药（青岛）有限公司 | Preparation method of fluoro-calcitol CD ring intermediate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10182597A (en) * | 1996-10-29 | 1998-07-07 | Sumitomo Pharmaceut Co Ltd | Isomerized vitamin d derivative |
| CN1201452A (en) * | 1995-10-31 | 1998-12-09 | 弗·哈夫曼-拉罗切有限公司 | 24-homo-26,27-hexafluoro-choleccalciferols |
| US5872113A (en) * | 1997-05-16 | 1999-02-16 | Syntex (U.S.A.) Inc. | Fluorinated vitamin D3 analogs |
| US5994569A (en) * | 1997-07-17 | 1999-11-30 | Hoffmann-La Roche Inc. | Dihomo-seco-cholestanes |
| CN1253557A (en) * | 1997-04-28 | 2000-05-17 | 弗·哈夫曼-拉罗切有限公司 | Vitamin D3 analogs with bis C-20 side chains |
| US20080280859A1 (en) * | 2005-10-19 | 2008-11-13 | Bioxell S.P.A. | Gemini vitamin d3 compounds and methods of use thereof |
| CN114044788A (en) * | 2021-08-12 | 2022-02-15 | 甘肃皓天医药科技有限责任公司 | Preparation method and application of fluorocalcitol CD ring |
-
2021
- 2021-12-30 CN CN202111654227.4A patent/CN114276284A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201452A (en) * | 1995-10-31 | 1998-12-09 | 弗·哈夫曼-拉罗切有限公司 | 24-homo-26,27-hexafluoro-choleccalciferols |
| JPH10182597A (en) * | 1996-10-29 | 1998-07-07 | Sumitomo Pharmaceut Co Ltd | Isomerized vitamin d derivative |
| CN1253557A (en) * | 1997-04-28 | 2000-05-17 | 弗·哈夫曼-拉罗切有限公司 | Vitamin D3 analogs with bis C-20 side chains |
| US5872113A (en) * | 1997-05-16 | 1999-02-16 | Syntex (U.S.A.) Inc. | Fluorinated vitamin D3 analogs |
| US5994569A (en) * | 1997-07-17 | 1999-11-30 | Hoffmann-La Roche Inc. | Dihomo-seco-cholestanes |
| US20080280859A1 (en) * | 2005-10-19 | 2008-11-13 | Bioxell S.P.A. | Gemini vitamin d3 compounds and methods of use thereof |
| CN114044788A (en) * | 2021-08-12 | 2022-02-15 | 甘肃皓天医药科技有限责任公司 | Preparation method and application of fluorocalcitol CD ring |
Non-Patent Citations (1)
| Title |
|---|
| SHIAN-JAN SHIUEY 等: "Triply Convergent Synthesis of lar,25-Dihydroxy-24(R)-fluorocholecalciferol", 《J. ORG. CHEM.》, vol. 53, no. 5, pages 1040 - 1046, XP002152696, DOI: 10.1021/jo00240a021 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114656384A (en) * | 2022-04-20 | 2022-06-24 | 正大制药（青岛）有限公司 | Preparation method of eldecalcitol 20S isomer |
| CN116354790A (en) * | 2023-02-14 | 2023-06-30 | 正大制药（青岛）有限公司 | Preparation method of fluoro-calcitol CD ring intermediate |
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