CN116354790A - Preparation method of fluoro-calcitol CD ring intermediate - Google Patents
Preparation method of fluoro-calcitol CD ring intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims abstract description 67
- 229940125904 compound 1 Drugs 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- 229940126214 compound 3 Drugs 0.000 claims abstract description 19
- 229940125782 compound 2 Drugs 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 11
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- -1 isopropyl ester Chemical class 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 230000004224 protection Effects 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 6
- 238000003682 fluorination reaction Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VUSMHPJJFLCUOR-UHFFFAOYSA-N 1,1,1-trifluoro-2-(trifluoromethyl)but-3-en-2-ol Chemical compound C=CC(O)(C(F)(F)F)C(F)(F)F VUSMHPJJFLCUOR-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000004334 fluoridation Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001668 calcitriol derivatives Chemical class 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
-
- 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
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of organic chemistry, and particularly discloses a preparation method of a fluoro-calcitol CD ring intermediate, which comprises the following steps: step one: reacting the compound 1 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst, and purifying to obtain a compound 2; step two: continuously reacting the compound 2 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst to obtain a compound 3; step three: deprotection of compound 3 in an organic solvent II under acidic conditions affords compound 4, the CD ring intermediate of the fluoro-calcitol. The invention has the advantages that TMSCF is adopted for the first time 3 And TBAF fluorination system to prepare the fluoro-calcitol CD ring intermediate, avoiding using toxic fluorination reagent and virulent protection reagent, having the advantages of cheap and easily available raw materials, short route, simple operation, environmental protection and high yield, the total yield of the route is above 77%, and being suitable for industrial productionRequirements.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of a fluoro-calcitol CD ring intermediate.
Technical Field
Fluorocalcitol (Falecalcitradiol), a calcitriol analog developed by a combination of Dazheng (Taisho), kissei and Dajapanese Sumitomo (Dainippon Sumitomo), has higher potency both in vivo and in vitro and longer duration of action in vivo. The composition can improve bone diseases and symptoms caused by vitamin D deficiency, and can be used for promoting absorption to supplement deficient calcium and prevent osteoporosis. Can be used for treating secondary hyperparathyroidism, hypoparathyroidism, rickets and osteomalacia of patients during dialysis.
The CD ring intermediate of the fluocalcitol is a key starting material for preparing the fluocalcitol by adopting a convergent route. The intermediate of the CD ring of the fluoro-calcitol is subjected to secondary hydroxyl oxidation and tertiary hydroxyl protection, then is subjected to coupling reaction with the A ring, and then is subjected to deprotection reaction to obtain the fluoro-calcitol. The chemical synthesis route is as follows (formula 2):
According to literature reports, the preparation methods of the prior fluoro-calcitol CD ring intermediate mainly comprise two methods, namely the following steps:
(1) Patent CN111960938A reports (as shown in formula 3), tert-butyl acetate and hexafluoroacetone are used as raw materials, and the fluoro-calcitol CD ring intermediate is obtained through 9 steps of reactions such as condensation, upper protection, reduction, iodination, coupling, deprotection and the like.
(2) Patent CN112047820a reports (as formula 4), that short-chain CD ring iodides and 2-vinyl hexafluoroisopropanol are used as raw materials, and the fluoro-calcitol CD ring intermediate is obtained through 4 steps of reaction of coupling, upper protection, deprotection and oxidation, the raw materials of the fluoridation reagent 2-vinyl hexafluoroisopropanol in the route do not realize commercial production with extremely high price, the hydroxyl protecting group uses extremely toxic MOMCl, the yield is low, and the total yield is 18.4%, so the route also does not meet the requirement of industrial production.
Therefore, the invention discloses a novel preparation method of a fluoro-calcitol CD ring intermediate, which aims to solve the problems of the existing fluoro-calcitol CD ring intermediate that a highly toxic reagent is used in the preparation process, the yield is low, the reaction condition is harsh, and the like, and is not suitable for the requirements of industrial production.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of a fluoro-calcitol CD ring intermediate, which comprises the following steps:
step one: reacting the compound 1 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst, and purifying to obtain a compound 2;
step two: continuously reacting the compound 2 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst to obtain a compound 3;
step three: deprotection of compound 3 in an organic solvent II under acidic conditions to give compound 4;
compound 2 has the structure shown below:
compound 4 has the structure shown below:
wherein, the compound 4 is a fluoro-calcitol CD ring intermediate;
wherein the side chain ester group structure of the compound 1 is any one of ethyl ester, methyl ester, isopropyl ester or butyl ester;
wherein, TBS can be replaced by TMS, TES, TBDPS, DIPS, DPS or TIPDS.
In some embodiments, in step one or step two, the organic solvent one is any one or more of tetrahydrofuran, N-dimethylformamide, N-pentane, N-hexane, N-heptane, diethyl ether, dimethyl ether, methyl tert-butyl ether.
In some embodiments, the reaction temperature is 20-30 ℃ in the first or second step.
In some embodiments, in the first or second step, the molar value of the compound 1, (trifluoromethyl) trimethylsilane and tetrabutylammonium fluoride is 1 (1.1-10): 0.05-1.
In some embodiments, the first or second step further comprises: after the reaction is completed, adding water to quench the reaction, and adding 1-5 times of compound 1 molar quantity of tetrabutylammonium fluoride to perform the reaction.
In some embodiments, in the third step, the organic solvent two is one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, dichloromethane, and ethyl acetate.
In some of these embodiments, the acid used for deprotection is one or more of methane sulfonic acid, sulfuric acid, hydrofluoric acid, hydrochloric acid.
In some embodiments, in the third step, the reaction temperature is 15-60 ℃.
The invention also provides an application of any one of the compound 1, the compound 2 or the compound 3 in preparing a CD ring intermediate of the fluoro-calcitol or preparing a CD ring intermediate product of the fluoro-calcitol.
The invention also provides an application of any one of the methods in preparing a fluoro-calcitol CD ring intermediate.
The invention also provides a fluoro-calcitol CD ring intermediate which is prepared by any one of the methods.
Compared with the prior art, the invention has the beneficial effects that: TMSCF is adopted for the first time 3 And TBAF fluorination system to prepare the fluoro-calcitol CD ring intermediate, avoiding using toxic fluorination reagent, having the advantages of cheap and easily available raw materials, short route, simple operation, environmental protection and high yield, the total yield of the route is above 77%, and being suitable for the requirement of industrial production.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 4;
FIG. 2 is a nuclear magnetic resonance fluorine spectrum of Compound 4.
Detailed Description
According to literature reports, the preparation methods of the prior fluoro-calcitol CD ring intermediate mainly comprise two methods, namely the following steps:
(1) Patent CN111960938A reports (as shown in formula 3), tert-butyl acetate and hexafluoroacetone are used as raw materials, and the fluoro-calcitol CD ring intermediate is obtained through 9 steps of reactions such as condensation, upper protection, reduction, iodination, coupling, deprotection and the like.
(2) Patent CN112047820a reports (as formula 4), that short-chain CD ring iodides and 2-vinyl hexafluoroisopropanol are used as raw materials, and the fluoro-calcitol CD ring intermediate is obtained through 4 steps of reaction of coupling, upper protection, deprotection and oxidation, the raw materials of the fluoridation reagent 2-vinyl hexafluoroisopropanol in the route do not realize commercial production with extremely high price, the hydroxyl protecting group uses extremely toxic MOMCl, the yield is low, and the total yield is 18.4%, so the route also does not meet the requirement of industrial production.
Therefore, aiming at the problems of using extremely toxic reagent, low yield, harsh reaction conditions, unsuitable industrial production requirements and the like in the preparation process of the fluoro-calcitol CD ring intermediate, the invention provides the method for preparing the fluoro-calcitol CD ring intermediate by adopting TMSCF 3 And a synthesis process for preparing the fluoro-calcitol CD ring intermediate by a TBAF fluorination system. The technical scheme adopted is as follows (formula 1):
Step one: compound 1 is reacted with (trifluoromethyl) Trimethylsilane (TMSCF) in the presence of tetrabutylammonium fluoride (TBAF) in an organic solvent 3 ) Reacting and purifying to obtain the compound 2.
The method comprises the following steps: dissolving a compound 1 in a solvent I under the protection of nitrogen to form a solution with the concentration of 0.3-0.6 mol/L, and adding TMSCF 3 And TBAF, reacting for 4-6 hours at 20-30 ℃, adding water to quench TMSCF 3 Adding TBAF, stirring for 10min, washing with water, drying, concentrating, purifying to obtain compound 2;
TMSCF in step one 3 The molar charge amount of (2) may be 1.1 to 10 times, preferably 3 times, that of compound 1; the catalytic amount of TBAF may be the hydrate of TBAF or a solution of TBAF in tetrahydrofuran, preferably TBAF in tetrahydrochyseneThe furan solution can have a molar charge equivalent of 0.05 to 1 times, preferably 0.1 times that of compound 1; the molar amount of TBAF after quenching is 1-5 times, preferably 1 time that of the compound 1; the organic solvent I can be any one or more of tetrahydrofuran, N-dimethylformamide, N-pentane, N-hexane, N-heptane, diethyl ether, dimethyl ether and methyl tertiary butyl ether, and more preferably N-pentane.
Step two: compound 2 was reacted with TMSCF in organic solvent one under the catalysis of TBAF 3 The reaction was continued to give compound 3.
The method comprises the following steps: dissolving a compound 1 in a solvent I under the protection of nitrogen to form a solution with the concentration of 0.3-0.6 mol/L, and adding TMSCF 3 And TBAF (Tunnel boring mill), reacting for 4-6 hours at 20-30 ℃, adding water to quench TMSCF (TMSCF) 3 Adding TBAF, stirring for 10min, washing with water, drying, concentrating, purifying to obtain compound 3;
TMSCF in step two 3 The molar charge amount of (2) may be 1.1 to 10 times, preferably 3 times, that of compound 1; the catalytic amount of TBAF can be hydrate of TBAF or tetrahydrofuran solution of TBAF, preferably tetrahydrofuran solution of TBAF, and the molar charge equivalent can be 0.05-1 times, preferably 0.1 times of that of the compound 1; the molar amount of TBAF after quenching is 1-5 times, preferably 1 time that of the compound 1; the organic solvent I can be any one or more of tetrahydrofuran, N-dimethylformamide, N-pentane, N-hexane, N-heptane, diethyl ether, dimethyl ether and methyl tertiary butyl ether, and more preferably N-pentane.
Step three: deprotection of compound 3 in organic solvent two under acidic conditions gives compound 4 (the fluoro-calcitol CD ring intermediate).
The method comprises the following steps: dissolving the compound 3 in an organic solvent II to form a solution of 0.1-0.5 mol/L, adding an aqueous solution of an acid, stirring for 12-36 h at 25-60 ℃, and performing operations such as quenching by a sodium bicarbonate aqueous solution, extraction, water washing, drying, purification and the like to obtain a compound 4; specific acidic conditions are: the pH value is more than 7 and less than or equal to 8.5;
in the third step, the acid can be methane sulfonic acid, sulfuric acid, hydrofluoric acid, hydrochloric acid and the like, preferably a 20% hydrochloric acid aqueous solution, and the molar dosage of the acid can be 5-30 times, preferably 20 times, equivalent of the compound 3; the organic solvent II can be one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, dichloromethane and ethyl acetate, and is preferably a mixed solution of methanol and tetrahydrofuran.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: preparation of Compound 2
N 2 Under protection, 5.0g of 12.2mmol of Compound 1, 30mL of n-pentane, 5.2g of 36.6mmol of TMSCF 3 And 1.2mL of TBAF (1M in THF) were added to a 100mL three-necked flask, and the reaction was stirred at 25℃for 2 hours, and the reaction mixture finally became brown from pale yellow. TLC (developing solvent PE/ea=20:1) monitored that compound 1 was substantially completely reacted. The reaction was quenched by adding 10mL of water, 12mL of TBAF (1M in THF) was added at room temperature, the reaction was stirred for 10min, diluted with 150mL of EA, the organic phase was washed with water (100 mL. Times.3), and anhydrous MgSO 4 Drying, suction filtering, and concentrating the filtrate under reduced pressure. Purifying by a silica gel column, wherein the ratio of the eluent n-hexane to EA is 20:1, compound 2 was obtained as a pale yellow oily product 5.2g in 96% yield.
Example 2: preparation of Compound 3
N 2 Under protection, 5.2g of 11.9mmol of Compound 2, 30mL of n-pentane, 5.1g of 35.8mmol of TMSCF 3 And 1.2mL TBAF (1M in THF) was added to a 100mL three-necked flask, and the reaction was stirred at 25℃for 2 hours, whereby the reaction mixture eventually became yellow to yellow brown. TLC (developing solvent PE/ea=20:1) monitored compound 2 was substantially completely reacted. The reaction was quenched by the addition of water (10 mL), 12mL of TBAF (1M in THF) was added at room temperature, the reaction was stirred for 10min, diluted with 150mL of EA, the organic phase was washed with water (100 mL. Times.3), anhydrous MgSO 4 Drying, suction filtering, and collectingThe filtrate was concentrated under reduced pressure. Purifying by a silica gel column, wherein the ratio of the eluent n-hexane to EA is 20:1, 5.7g of compound 3 was obtained as a yellow oil in 95% yield.
Example 3: preparation of Compound 4
N 2 5.7g of 11.3mmol of Compound 3, 20mL of THF and 20mL of methanol were added under protection to a 100mL reaction flask, 37.5mL of 20% hydrochloric acid (226 mmol) was added, the reaction was stirred at room temperature for 30h, TLC (developer PE/EA=5:1) monitored that Compound 3 was substantially completely reacted, diluted with 100mL of DCM, and saturated NaHCO was slowly added 3 The solution was adjusted to ph=8, the organic phase was washed with water (100 ml×3) to neutrality, anhydrous MgSO 4 Drying, suction filtering, concentrating the filtrate under reduced pressure to dryness, adding n-hexane according to the proportion of 15mL/g, heating to 48 ℃ for stirring and dissolving, transferring to room temperature environment for slow cooling crystallization for 1h after dissolving, transferring to-5 ℃ for stirring crystallization for 4h, suction filtering the solid, and vacuum drying at room temperature to obtain 3.8g of white powder solid with the yield of 85%.
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 4, with the following results:
1 H NMR(CDCl 3 ): δ(ppm) : 4.08 (s, H), 3.05(s, H), 2.01 (d, H), 1.92 (m, H), 1.82-1.85 (m, 4H), 1.55 (m, 2H), 1.45-1.40(m, 5H), 1.35-1.34 (m, 2H), 1.29-1.27 (m, 2H), 1.88 (m, H), 1.08 (m, 2H), 0.93(s, 3H), 0.91 (d, 3H).
FIG. 2 is a nuclear magnetic resonance fluorine spectrum of Compound 4, with the following results:
19 F NMR(CDCl 3 ): δ(ppm) : -76.54 (CF 3 );-76.69 (CF 3 ).
the foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and substitutions can be made by those skilled in the art without departing from the technical principles of the present invention, and these modifications and substitutions should also be considered as being within the scope of the present invention.
Claims (10)
1. A method for preparing a CD ring intermediate of a fluoro-calcitol, the method comprising:
step one: reacting the compound 1 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst, and purifying to obtain a compound 2;
step two: continuously reacting the compound 2 with (trifluoromethyl) trimethylsilane in an organic solvent I by using tetrabutylammonium fluoride as a catalyst to obtain a compound 3;
step three: deprotection of compound 3 in an organic solvent II under acidic conditions to give compound 4;
compound 1 has the structure shown below:
compound 2 has the structure shown below:
compound 3 has the structure shown below:
compound 4 has the structure shown below:
wherein, the compound 4 is a fluoro-calcitol CD ring intermediate;
wherein the side chain ester group structure of the compound 1 is any one of ethyl ester, methyl ester, isopropyl ester or butyl ester;
wherein, TBS can be replaced by TMS, TES, TBDPS, DIPS, DPS or TIPDS.
2. The method according to claim 1, wherein in the first or second step, the first organic solvent is any one or more of tetrahydrofuran, N-dimethylformamide, N-pentane, N-hexane, N-heptane, diethyl ether, dimethyl ether and methyl tert-butyl ether.
3. The method according to claim 1, wherein in the first or second step, the reaction temperature is 20 to 30 ℃.
4. The method according to claim 1, wherein in the first or second step, the molar ratio of the compound 1, (trifluoromethyl) trimethylsilane to tetrabutylammonium fluoride is 1 (1.1-10): 0.05-1.
5. The method of claim 1, wherein step one or step two further comprises: after the reaction is completed, adding water to quench the reaction, and adding 1-5 times of compound 1 molar quantity of tetrabutylammonium fluoride to perform the reaction.
6. The method according to claim 1, wherein in the third step, the second organic solvent is one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, dichloromethane and ethyl acetate;
the acid used for deprotection is one or more of methane sulfonic acid, sulfuric acid, hydrofluoric acid and hydrochloric acid.
7. The method according to any one of claims 1 to 6, wherein in step three, the reaction temperature is 15 to 60 ℃.
8. Use of compound 1, compound 2 or compound 3 according to any one of claims 1 to 7 for the preparation of a CD ring intermediate of or for the preparation of a CD ring intermediate product of f-calcitol.
9. Use of a process according to any one of claims 1 to 7 in the preparation of a CD ring intermediate of a fluoro-calcitol.
10. A fluoroacalcitol CD ring intermediate prepared by the process of any one of claims 1-7.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006242184A1 (en) * | 2005-05-03 | 2006-11-09 | Wisconsin Alumni Research Foundation | 19,26,27-trinor-1alpha,25-dihydroxyvitamin D3 compounds |
| CN112047820A (en) * | 2020-08-20 | 2020-12-08 | 甘肃皓天医药科技有限责任公司 | Preparation method and application of fluorocalcitol intermediate |
| 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 |
| CN114276284A (en) * | 2021-12-30 | 2022-04-05 | 正大制药（青岛）有限公司 | A kind of preparation method of fluorocalcidol |
| CN114957068A (en) * | 2022-04-19 | 2022-08-30 | 正大制药（青岛）有限公司 | Preparation method of fluorcalciferol 20S isomer |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006242184A1 (en) * | 2005-05-03 | 2006-11-09 | Wisconsin Alumni Research Foundation | 19,26,27-trinor-1alpha,25-dihydroxyvitamin D3 compounds |
| CN112047820A (en) * | 2020-08-20 | 2020-12-08 | 甘肃皓天医药科技有限责任公司 | Preparation method and application of fluorocalcitol intermediate |
| 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 |
| CN114276284A (en) * | 2021-12-30 | 2022-04-05 | 正大制药（青岛）有限公司 | A kind of preparation method of fluorocalcidol |
| CN114957068A (en) * | 2022-04-19 | 2022-08-30 | 正大制药（青岛）有限公司 | Preparation method of fluorcalciferol 20S isomer |
Non-Patent Citations (1)
| Title |
|---|
| 赵洺良等: "维生素D类药物及其类似物的研发进展", 《中国骨质疏松杂志》, vol. 27, no. 06, pages 914 - 921 * |
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