CN112094291A - Synthesis method of adicalcitol A ring intermediate - Google Patents
Synthesis method of adicalcitol A ring intermediate Download PDFInfo
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- CN112094291A CN112094291A CN202010816304.0A CN202010816304A CN112094291A CN 112094291 A CN112094291 A CN 112094291A CN 202010816304 A CN202010816304 A CN 202010816304A CN 112094291 A CN112094291 A CN 112094291A
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- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 24
- 229950005556 eldecalcitol Drugs 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 17
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 10
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000011261 inert gas Substances 0.000 claims abstract description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- FZEXGDDBXLBRTD-SJSKTVLPSA-N eldecalcitol 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@H](OCCCO)[C@@H](O)C1=C FZEXGDDBXLBRTD-SJSKTVLPSA-N 0.000 claims abstract 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000012043 crude product Substances 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- -1 p-methoxybenzyl Chemical group 0.000 claims description 3
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- FZEXGDDBXLBRTD-AYIMTCTASA-N 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 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@@H](OCCCO)[C@H](O)C1=C FZEXGDDBXLBRTD-AYIMTCTASA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 3
- 229960002535 alfacalcidol Drugs 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
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Classifications
-
- 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
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of an idecalcitol A ring intermediate, belonging to the technical field of organic chemistry, and the synthesis method comprises the following steps of (1) dissolving a compound I in an organic solvent, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone, and obtaining a compound II after the reaction is finished; (2) dissolving a compound II in an organic solvent, and reacting the compound II with tert-butyldimethylsilyl chloride under the condition of organic alkali to obtain a compound III under the inert gas condition; (3) dissolving a compound VI in an organic solvent, cooling under inert gas, adding butyl lithium, then sequentially adding a compound III and boron trifluoride diethyl etherate, and reacting to obtain a compound IV; (4) dissolving a compound IV in an organic solvent, and reacting the compound IV with tert-butyldimethylsilyl chloride under the condition of organic alkali under the inert gas to obtain a compound V; the method for synthesizing the eldecalcitol intermediate is simple and efficient to operate, is beneficial to large-scale production, and the prepared A ring is easy to separate and purify and has high purity.
Description
Technical Field
A synthetic method of an eldecalcitol A ring intermediate belongs to the technical field of organic chemistry, and particularly relates to preparation of a medical intermediate.
Background
The product is Edirol, which is a drug developed by combining external pharmacy in Japan and large pharmacy and used for treating osteoporosis, is marketed in Japan in 2011, is a new active vitamin D3 derivative used for treating osteoporosis after alfacalcidol, and has the advantages that the curative effect is better than that of alfacalcidol, the safety is similar to that of alfacalcidol, and the product has wide application prospect; the chemical structural formula is as follows:
according to the currently reported synthetic routes, the following methods are mainly used for preparing the eldecalcitol by multi-step linear synthesis and final photoreaction, wherein lithocholic acid or cholesterol is used as a raw material like a vitamin D analogue. The method has the advantages of expensive initial raw materials, low total yield, ring opening by light reaction and thermal isomerization reaction, more product impurities and purification by preparative chromatography. Secondly, a molecular skeleton is constructed by utilizing a Trost coupling reaction. And thirdly, respectively synthesizing an A ring and a CD ring, and synthesizing the eldecalcitol by gathering through Horner-Wadsworth-Emmons reaction, wherein the total yield is high, and the product quality is easy to control. At present, the third method is mostly adopted for preparing the eldecalcitol in a large scale. Therefore, it is important how to synthesize the A ring in high yield and high selectivity.
In original research, foreign pharmaceuticals in japan in journal heterocylies, 2006,70,295 reported the following a-ring synthesis method, which is as follows:
according to the method, D-diethyl tartrate is used as a raw material, a C2 symmetric epoxy compound is prepared, and a key intermediate A ring is obtained through multi-step conversion, but the selectivity is poor, the total yield is low, and great difficulty is caused for final separation and purification.
Another synthesis of ring a is reported in Tetrahedron,2015,71,8033, which is a synthetic route as follows:
the route takes D-mannitol as a chiral source, although the selectivity of the product is greatly improved and the yield is also improved, the whole route needs 18 steps of linear steps and is relatively complicated.
Patent WO2018093223 discloses a preparation method of an eldecalcitol a ring, and the synthetic route is as follows:
the route takes D-mannitol as a chiral source, although the stereoselectivity of the product is greatly improved, 1-position and 3-position isomers are still generated in the reaction process, and the product cannot be separated and purified, and is only purified by preparative chromatography.
Another A-ring synthesis method is reported in Tetrahedron,2020,76,131081, and the synthesis route is as follows:
the route also takes D-mannitol as a chiral source, and key intermediates are synthesized through 14 steps of linear steps, but a 2-position side chain is introduced through tert-butyl ester, lithium aluminum hydrogen is required for reduction, and great potential safety hazard exists.
In conclusion, in the prior art, the synthesis route of the alditol intermediate A ring is long, the difficulty is high, the purity is low, and therefore the production cost is high. Based on the above, the invention provides a method for synthesizing an eldecalcitol A ring intermediate, which can simultaneously obtain a high-yield and high-purity key intermediate, and the high-purity A ring is prepared from the key intermediate.
Disclosure of Invention
The invention aims to: the synthesis method of the eldecalcitol A ring intermediate is simple and efficient to operate, is beneficial to large-scale production, is high in yield and purity of the obtained key intermediate V, prepares the A ring, enables the purity of a crude product to be more than 98.0%, can be more than 99.0% through simple column purification, enables 1-position and 3-position isomers to be controlled to be less than 0.1%, and is simpler and easier to separate and purify and high in product purity.
The technical scheme adopted by the invention is as follows:
in order to achieve the above object, the present invention provides a method for synthesizing an eldecalcitol a ring intermediate, comprising the steps of:
(1) dissolving a compound I in an organic solvent, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone, processing after stirring reaction to obtain a crude product, and performing column chromatography to obtain a compound II, wherein the structural formula of the compound I is as follows:
(2) dissolving a compound II in an organic solvent, and reacting the compound II with tert-butyldimethylsilyl chloride under the protection of inert gas under the condition of organic alkali to obtain a compound III;
(3) dissolving a compound VI in an organic solvent, cooling under the protection of inert gas, adding butyl lithium, then sequentially adding a compound III and boron trifluoride diethyl etherate, wherein the reaction temperature is-100-0 ℃, and reacting to obtain a compound IV, wherein the structural formula of the compound VI is as follows:
(4) dissolving a compound IV in an organic solvent, and reacting the compound IV with tert-butyldimethylsilyl chloride under the protection of inert gas under the condition of organic alkali to obtain a compound V.
Preferably, R is1Is tert-butyl dimethyl silicon base, tert-butyl diphenylSilyl, triisopropylsilyl, methoxymethyl or ethoxyethyl.
Preferably, R is1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base or methoxymethyl.
Preferably, R is2Is tetrahydropyranyl or p-methoxybenzyl.
Preferably, the organic solvent in step (1) is a mixed solvent of water and any one of dichloromethane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran and dioxane.
Preferably, the organic solvent in the step (1) is a mixed solvent of dichloromethane and water, wherein the volume ratio of dichloromethane to water is 10: 1.
preferably, the organic solvent in step (3) is selected from any one or more of diethyl ether, n-hexane, tetrahydrofuran, methyl tert-butyl ether and toluene.
Preferably, the reaction temperature in the step (3) is-80 ℃ to-50 ℃.
Preferably, the structural formulas of the compound II, the compound III and the compound IV are respectively as follows:
preferably, the compound v has the structural formula:
in summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:
the method for synthesizing the eldecalcitol intermediate is simple and efficient to operate and is beneficial to large-scale production; meanwhile, the high-purity key intermediate V is obtained with high yield, and then the A ring is prepared, the purity of the crude product can reach more than 98.0 percent, the purity can reach more than 99.0 percent through simple column purification, and the 1-position isomer and the 3-position isomer can be controlled below 0.1 percent, so that the separation and the purification are simpler and easier, and the product purity is high.
Drawings
The invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a synthetic scheme of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is to be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without any creative work belong to the protection scope of the present invention, and all experimental methods used in the following embodiments are conventional methods unless otherwise specified.
Example 1
The embodiment provides a method for synthesizing an eldecalcitol a ring intermediate, wherein a synthetic route is shown in fig. 1, and the method specifically comprises the following steps:
(1) preparation of Compound II
Compound I (75.0g, 0.177moL) was dissolved in 750mL of dichloromethane in a 2000mL three-necked flask under argon, 75mL of water was added, and 2, 3-dichloro-5, 6-dicyanobenzoquinone (44.3g, 0.195moL) was added. The reaction mixture was stirred for 30 minutes, filtered through celite, the filtrate was added with aqueous sodium bicarbonate and stirred for 2 minutes, left to stand for stratification, the organic phase was dried and concentrated to give a crude product, which was chromatographed using ethyl acetate and n-heptane to give compound ii (45.6g) in 85% yield.
(2) Preparation of Compound III
Under the protection of argon, dissolving a compound II (45.6g, 0.15moL) in 760mLN, N-dimethylformamide in a 2000mL three-necked flask, adding imidazole (40.8g, 0.6moL), adding tert-butyldimethylsilyl chloride (45.0g, 0.3moL) at 0 ℃, stirring for 1 hour, detecting the reaction by TLC, adding the reaction solution into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, drying and concentrating to obtain a crude product, and performing column chromatography on the crude product to obtain a compound III (56.61g), wherein the yield is 90%.
(3) Preparation of Compound IV
Compound VI (31.67g, 0.18moL) was dissolved in 500mL of tetrahydrofuran in a 2000mL three-necked flask under argon, cooled to-78 deg.C, n-butyllithium (72.0mL, 0.18moL) was added dropwise, stirred for 30 minutes, a tetrahydrofuran solution of compound III (25.0g, 0.06moL) was added, boron trifluoride ether (9.4g, 0.066moL) was added, and stirred for 30 minutes. Adding saturated sodium bicarbonate water solution, extracting with ethyl acetate, drying, concentrating to obtain crude product, and performing column chromatography to obtain compound IV (22.5g) with yield of 70%.
(4) Preparation of Compound V
Under the protection of argon, a compound IV (22.5g, 0.038moL) is dissolved in 225mLN, N-dimethylformamide in a 500mL three-necked flask, imidazole (10.34g, 0.152moL) is added, tert-butyldimethylchlorosilane (17.1g, 0.114moL) is added at 0 ℃ and stirred for 1 hour, TLC detection reaction is finished, the reaction solution is added into an aqueous solution of sodium bicarbonate, ethyl acetate is used for extraction, drying and concentration are carried out to obtain a crude product, and the crude product is subjected to column chromatography to obtain a compound V (23g), wherein the yield is 87%.
In this example, compound i as a raw material can be prepared by referring to the preparation method of patent WO2018093223, compound v prepared in this example can be used as an intermediate for preparing ring a by referring to the method reported in journals, Heterocycles,2006,70,295; in addition, R in this embodiment1Is tert-butyl dimethylsilyl radical, R2Is p-methoxybenzyl.
Example 2
The embodiment provides a method for synthesizing an eldecalcitol a ring intermediate, wherein a synthetic route is shown in fig. 1, and the method specifically comprises the following steps:
(1) preparation of Compound II
Compound I (50.0g, 0.142moL) was dissolved in 500mL of methylene chloride in a 1000mL three-necked flask under argon, 50mL of water was added, and 2, 3-dichloro-5, 6-dicyanobenzoquinone (38.5g, 0.170moL) was added. The reaction mixture was stirred for 30 minutes, filtered through celite, the filtrate was added with aqueous sodium bicarbonate and stirred for 2 minutes, left to stand for stratification, the organic phase was dried and concentrated to give a crude product, which was chromatographed using ethyl acetate and n-heptane to give compound ii (27g) in 81.8% yield.
(2) Preparation of Compound III
Under the protection of argon, dissolving a crude compound II (25.0g, 0.108moL) in 250mLN, N-dimethylformamide in a 500mL three-necked flask, adding imidazole (22g, 0.32moL), adding tert-butyldimethylsilyl chloride (32.4g, 0.216moL) at 0 ℃, stirring for 1 hour, detecting the reaction by TLC, adding the reaction solution into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, drying and concentrating to obtain a crude product, and performing column chromatography to obtain a compound III (56.61g), wherein the yield is 80.6%.
(3) Preparation of Compound IV
Compound VI (36.4g, 0.26moL) was dissolved in 400mL of diethyl ether in a 2000mL three-necked flask under the protection of argon, cooled to-70 ℃, n-butyllithium (104mL, 0.26moL) was added dropwise, stirred for 30 minutes, compound III (30.0g, 0.087moL) was added, boron trifluoride diethyl etherate (13.6g, 0.095moL) was added, and stirred for 30 minutes. Adding saturated sodium bicarbonate water solution, extracting with ethyl acetate, drying, concentrating to obtain crude product, and performing column chromatography to obtain compound IV (35.8g) with yield of 85%.
(4) Preparation of Compound V
Under the protection of argon, dissolving a compound IV (30g, 0.062moL) in 300mLN, N-dimethylformamide in a 500mL three-necked flask, adding imidazole (12.6g, 0.185moL), adding TBSCl (18.6g, 0.124moL) at 0 ℃, stirring for 1 hour, detecting the reaction by TLC, adding a reaction solution into an aqueous solution of sodium bicarbonate, extracting with ethyl acetate, drying and concentrating to obtain a crude product, and performing column chromatography to obtain a compound V (30.9g) with the yield of 83%.
In this example, the compound i is used as a raw material and can be prepared by referring to a preparation method of patent WO2018093223, and the compound v prepared in this example is used as an intermediate for preparing ring a and can be prepared by referring to a method reported in journals, Heterocycles,2006,70,295; in addition, R in this embodiment1Is methoxymethyl, R2Is tetrahydropyranyl.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; these modifications and substitutions do not cause the essence of the corresponding technical solution to depart from the scope of the technical solution of the embodiments of the present invention, and are intended to be covered by the claims and the specification of the present invention.
Claims (10)
1. A method for synthesizing an eldecalcitol A ring intermediate is characterized by comprising the following steps:
(1) dissolving a compound I in an organic solvent, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone, processing after stirring reaction to obtain a crude product, and performing column chromatography to obtain a compound II, wherein the structural formula of the compound I is as follows:
(2) dissolving a compound II in an organic solvent, and reacting the compound II with tert-butyldimethylsilyl chloride under the protection of inert gas under the condition of organic alkali to obtain a compound III;
(3) dissolving a compound VI in an organic solvent, cooling under the protection of inert gas, adding butyl lithium, then sequentially adding a compound III and boron trifluoride diethyl etherate, wherein the reaction temperature is-100-0 ℃, and reacting to obtain a compound IV, wherein the structural formula of the compound VI is as follows:
(4) dissolving a compound IV in an organic solvent, and reacting the compound IV with tert-butyldimethylsilyl chloride under the protection of inert gas under the condition of organic alkali to obtain a compound V.
2. The digalciferol A-ring intermediate of claim 1A method for synthesizing a compound represented by the formula R1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, methoxymethyl or ethoxyethyl.
3. The method for synthesizing the eldecalcitol A ring intermediate as claimed in claim 1, wherein R is1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base or methoxymethyl.
4. The method for synthesizing the eldecalcitol A ring intermediate as claimed in claim 1, wherein R is2Is tetrahydropyranyl or p-methoxybenzyl.
5. The method for synthesizing the eldecalcitol A ring intermediate as claimed in claim 1, wherein the organic solvent used in step (1) is a mixed solvent of water and any one of dichloromethane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran and dioxane.
6. The method for synthesizing the eldecalcitol A ring intermediate according to claim 1, wherein the organic solvent in step (1) is a mixed solvent of dichloromethane and water, wherein the volume ratio of dichloromethane to water is 10: 1.
7. the method for synthesizing the eldecalcitol A ring intermediate as claimed in claim 1, wherein the organic solvent in step (3) is selected from any one or more of diethyl ether, n-hexane, tetrahydrofuran, methyl tert-butyl ether and toluene.
8. The method for synthesizing the eldecalcitol A ring intermediate as claimed in claim 1, wherein the reaction temperature in step (3) is-80 ℃ to-50 ℃.
9. The method for synthesizing the eldecalcitol A ring intermediate as claimed in any one of claims 1 to 8, wherein the structural formulas of the compound II, the compound III and the compound IV are respectively:
10. the method for synthesizing the eldecalcitol A ring intermediate as claimed in any one of claims 1 to 8, wherein the compound V has a structural formula:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10251183A (en) * | 1997-03-07 | 1998-09-22 | Chugai Pharmaceut Co Ltd | Synthetic intermediate useful for synthesizing a-ring moiety of vitamin d derivative, its production and usage thereof |
| CN109982992A (en) * | 2016-11-21 | 2019-07-05 | 研成精密化学株式会社 | The preparation method of Chinese mugwort ground ostelin and intermediate for it |
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2020
- 2020-08-14 CN CN202010816304.0A patent/CN112094291A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10251183A (en) * | 1997-03-07 | 1998-09-22 | Chugai Pharmaceut Co Ltd | Synthetic intermediate useful for synthesizing a-ring moiety of vitamin d derivative, its production and usage thereof |
| CN109982992A (en) * | 2016-11-21 | 2019-07-05 | 研成精密化学株式会社 | The preparation method of Chinese mugwort ground ostelin and intermediate for it |
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| Title |
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| GUODONG ZHAO ET AL.,: "Structural revisions of the reported A-ring phosphine oxide synthon for ED-71 (Eldecalcitol) and a new synthesis", 《TETRAHEDRON》 * |
| JUNJI MAEYAMA ET AL.,: "TWO CONVERGENT APPROACHES TO THE SYNTHESIS OF 1α,25-DIHYDROXY-2β-(3-HYDROXYPROPOXY)VITAMIN D3 (ED-71) BY THE LYTHGOE AND THE TROST COUPLING REACTION", 《HETEROCYCLES》 * |
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