CN114920733B - Method for synthesizing chiral isoxazole ring and carbocyclic nucleoside analogue by cycloaddition - Google Patents
Method for synthesizing chiral isoxazole ring and carbocyclic nucleoside analogue by cycloaddition Download PDFInfo
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- CN114920733B CN114920733B CN202210572077.0A CN202210572077A CN114920733B CN 114920733 B CN114920733 B CN 114920733B CN 202210572077 A CN202210572077 A CN 202210572077A CN 114920733 B CN114920733 B CN 114920733B
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- lewis acid
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- 229940127073 nucleoside analogue Drugs 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 238000006352 cycloaddition reaction Methods 0.000 title claims abstract description 8
- 125000000842 isoxazolyl group Chemical group 0.000 title abstract description 8
- 125000002837 carbocyclic group Chemical group 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- -1 aryl enol ether Chemical class 0.000 claims abstract description 18
- 239000011968 lewis acid catalyst Substances 0.000 claims abstract description 12
- YKEOBJPDBNVCTJ-UHFFFAOYSA-N cyclopropane;pyrimidine Chemical compound C1CC1.C1=CN=CN=C1 YKEOBJPDBNVCTJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000002777 nucleoside Substances 0.000 claims description 16
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000002560 nitrile group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- PVWYOVVRIUUFIJ-UHFFFAOYSA-N 1,2-oxazole;pyrimidine Chemical compound C=1C=NOC=1.C1=CN=CN=C1 PVWYOVVRIUUFIJ-UHFFFAOYSA-N 0.000 description 1
- KTOLOIKYVCHRJW-XZMZPDFPSA-N 4-amino-1-[(2r,3s,4r,5r)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](F)[C@H](O)[C@](CO)(N=[N+]=[N-])O1 KTOLOIKYVCHRJW-XZMZPDFPSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- BZLZKLMROPIZSR-UHFFFAOYSA-N triphenylsilicon Chemical compound C1=CC=CC=C1[Si](C=1C=CC=CC=1)C1=CC=CC=C1 BZLZKLMROPIZSR-UHFFFAOYSA-N 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing chiral isoxazole ring and carbocyclic nucleoside analogues by cycloaddition, belonging to the technical field of medical intermediates. Chiral pyrimidine cyclopropane 1 and nitrosoaromatic 2 or aryl enol ether 5 are used as raw materials, and react in an organic solvent under the action of different Lewis acid catalysts to respectively obtain chiral isoxazole cyclic nucleoside analogues 3 or carbocyclic nucleoside analogues 6, wherein the reaction can be carried out in gram scale; when the Lewis acid catalyst is MgI 2 When the method is used, the yield reaches 78 percent and the ee is 88-96 percent, and the configuration of the cyclization reaction stereocenter is maintained; when the Lewis acid catalyst is Nd (OTf) 3 In the course of time, yields of up to 65% are obtained,>20:1dr and 87-96% ee.
Description
Technical Field
The invention relates to a method for synthesizing chiral isoxazole ring and carbocycle nucleoside analogues through [3+2] cycloaddition, belonging to the technical field of organic synthesis in medical intermediates.
Background
The optically active five-membered ring nucleoside compound generally has antiviral and antitumor activities and has wide application in pharmaceutical chemistry. Since the discovery of nucleosides having good antiviral activity, pyrimidine nucleoside synthesis has become a focus of research. Azvudine, stavudine, ji Duo vudine and troxacitabine are all relatively typical chiral five-membered ring pyrimidine nucleoside drugs.
At present, a synthesis method of chiral isoxazole ring or carbocyclic nucleoside, particularly synthesis of chiral isoxazole ring nucleoside is rarely reported, and chiral five-membered carbocyclic nucleoside is mainly concentrated in a pyrimidine base to introduce a chiral carbocycle. Under the action of Lewis acid, the [3+2] cycloaddition reaction between cyclopropane and unsaturated dipole is an effective method for constructing five-membered ring, but the [3+2] cyclization synthesis of chiral five-membered carbocyclic nucleoside by using racemic pyrimidine cyclopropane is very difficult, and a large amount of screening of chiral ligand, catalyst and the like is needed.
Therefore, there is a great need to develop a simple and efficient synthesis of chiral isoxazole rings and carbocyclic nucleosides.
Disclosure of Invention
In order to overcome the defects, the invention utilizes high chiral pure pyrimidine cyclopropane as a raw material, and synthesizes chiral isoxazole ring and carbocyclic nucleoside analogues with nitroso aromatic hydrocarbon or enol ether [3+2] ring under the action of Lewis acid catalyst. The method provides a high-efficiency and convenient way for synthesizing chiral isoxazole ring and carbocyclic nucleoside. In addition, the chiral isoxazole cyclic nucleoside is further reacted in the presence of inorganic base and sodium borohydride respectively, and the protecting group can be removed and the ester group can be reduced to obtain the novel chiral isoxazole cyclic nucleoside analogue.
The method for synthesizing chiral isoxazole cyclic nucleoside by cycloaddition comprises the following steps: chiral pyrimidine cyclopropane 1 and nitrosoaromatic hydrocarbon 2 are used as raw materials, and react in an organic solvent under the action of a Lewis acid catalyst to obtain a chiral isoxazole carbocyclic nucleoside analogue 3; the reaction scheme is as follows:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl; r is R 2 Selected from halogen, nitrile, nitro, trifluoromethyl, C1-C3 alkoxy ester.
Further toIn the above technical scheme, the Lewis acid catalyst is selected from MgBr 2 、 MgI 2 Etc., the best catalyst is MgI 2 。
Further, in the above technical scheme, the organic solvent is selected from one of dichloromethane, toluene, fluorobenzene, chlorobenzene and 1, 2-dichloroethane, and most preferably chlorobenzene.
Further, in the above technical scheme, the molar ratio of the chiral pyrimidine cyclopropane 1, the nitrosoaromatic hydrocarbon 2 and the lewis acid catalyst is 1:1-1.5:0.01-0.05.
Further, in the above technical scheme, the reaction temperature is-20 ℃ to 40 ℃, preferably-20 ℃.
Further, in the above technical scheme, the chiral isoxazole cyclic nucleoside 3 can be further derived, so that more types of chiral isoxazole cyclic nucleoside analogues are obtained. For example, removing the protecting group under the condition of inorganic base (potassium hydroxide, sodium carbonate and potassium carbonate) to obtain a product 8 or reducing the ester group under the action of sodium borohydride to obtain a product 9; the corresponding structures are as follows:
further, in the above technical scheme, the deprotection and reduction reactions are carried out in methanol.
The method for synthesizing the chiral carbocycle nucleoside analogue by cycloaddition comprises the following steps: chiral pyrimidine cyclopropane 1 and aryl enol ether 5 are used as raw materials, and react in an organic solvent under the action of a Lewis acid catalyst to obtain a chiral five-membered carbocyclic nucleoside analogue 6; the reaction equation is as follows:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl; r is R 3 Selected from halogen, methyl, methoxy, R 4 Selected from triisopropylsilane, trimethylSilicon-based, triethylsilane, triphenylsilicon-based, t-butyldimethylsilyl-based.
Further, in the above technical scheme, the catalyst is selected from SnCl 4 、Nd(OTf) 3 、 Cu(OTf) 2 、Er(OTf) 3 Etc., the best catalyst is Nd (OTf) 3 。
Further, in the above technical scheme, the organic solvent is selected from one of dichloromethane, chlorobenzene and 1, 2-dichloroethane, and the most preferred solvent is dichloromethane.
Further, in the above technical scheme, the reaction temperature is-20 ℃ to 30 ℃, preferably the reaction temperature is 0 ℃.
Further, in the above technical scheme, the molar ratio of the chiral pyrimidine cyclopropane 1, the aryl alkene alcohol ether 5 and the lewis acid catalyst is 1:1.2-6:0.02-0.05.
Detailed Description
Example 1:
[a]unless otherwise specified, the reaction conditions were 1a (0.05 mmol), 2a (0.06 mmol), lewis acid (20 mol%), solvent (1.0 mL) under nitrogen for 10 hours [ b ]]Isolation yield [ c ]]Confirmation by chiral HPLC analysis [ d ]]MgI 2 (10mol％).
In the screening process of the reaction conditions, the influence of the catalyst, the temperature and the solvent on the reaction is examined, and finally MgI is determined 2 For the optimal catalyst, the optimal reaction temperature was-20 ℃, and PhCl was selected as the optimal solvent.
Investigation of the reaction conditions:
chiral pyrimidine cyclopropane 1a (0.05 mmol,96% ee), nitrobenzene 2a (0.06 mmol,1.2 eq) and MgI were combined under nitrogen 2 (20 mol%) was dissolved in PhCl (1.0 mL) and the reaction was stirred at-20℃under controlled temperature. TLC monitoring of the progress of the reactionWater (1 mL) was added overnight and the mixture was extracted with DCM (3 mL. Times.3). The organic phases were combined, na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE/ea=2:1=2:1) to give 31.1mg of yellow solid 3aa;63% yield,94% ee [ alpha ]] D 20 ＝+65.4(c＝0.1,CH 2 Cl 2 ).R f ＝0.29 (Pet/EtOAc,2/1,v/v).m.p.:70.6-72.6℃.HPLC CHIRALCEL IF, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:23.946min,28.855min. 1 H NMR(600MHz,CDCl 3 )δ 7.93(d,J＝7.8Hz,2H),7.85(s,1H),7.65(t,J＝7.2Hz,1H),7.50(t,J＝ 7.8Hz,2H),7.41(t,J＝7.8Hz,2H),7.36-7.33(m,2H),7.21(t,J＝7.8 Hz,1H),6.52(dd,J＝7.8,3.6Hz,1H),3.84(s,3H),3.78(dd,J＝14.4, 7.8Hz,1H),3.40(s,3H),2.94(dd,J＝13.8,3.0Hz,1H),1.98(s,3H). 13 C NMR(150MHz,CDCl 3 )δ169.0,167.8,166.3,162.9,149.7,145.1, 135.5,135.2,131.7,130.7,129.3,128.7,126.5,120.4,111.5,82.0,53.6,52.9,46.3,13.0.HRMS(ESI):m/z calcd.for C 25 H 23 N 3 O 8 Na + [M+Na] + : 516.1377,found 516.1372.
Example 2:
according to the optimal reaction conditions in example 1, only the reaction substrates were changed, and the reaction results were as follows: [b] the reaction solvent is DCE, phCl=1:1; [c] the reaction time was 18 hours.
Typical compound characterization data are as follows:
3ab:White solid；62％yield,93％ee.[α] D 20 ＝+75.5(c＝0.2,CH 2 Cl 2 ).R f ＝0.33(Pet/EtOAc,2/1,v/v).m.p.:180.6-182.7℃.HPLC CHIRALCEL IF,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:16.312min,18.904min. 1 H NMR(600MHz,CDCl 3 )δ 7.94(d,J＝7.2Hz,2H),7.78(s,1H),7.66(t,J＝7.8Hz,1H),7.51(t,J＝ 7.8Hz,2H),7.41(s,1H),7.29-7.26(m,2H),7.20-7.17(m,1H),6.52(dd, J＝7.8,3.6Hz,1H),3.84(s,3H),3.77(dd,J＝14.4,7.8Hz,1H),3.48(s,3H),2.97(dd,J＝13.8,3.6Hz,1H),1.98(s,3H). 13 C NMR(150MHz, CDCl 3 )δ168.9,167.6,166.1,162.8,149.7,143.6,135.3,131.8,131.6, 130.7,129.3,128.8,121.8,121.8,111.7,81.9,53.7,53.1,46.1,29.8,13.0.HRMS(ESI):m/z calcd.for C 25 H 22 ClN 3 O 8 Na + [M+Na] + :550.0988, found 550.0991.
3ba:Colorless oil；54％yield,92％ee.[α] D 20 ＝+54.1(c＝0.6,CH 2 Cl 2 ). R f ＝0.43(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL ID,n-hexane /2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:21.907min,24.690min. 1 H NMR(600MHz,CDCl 3 )δ8.15(d,J＝6.0 Hz,1H),7.94(d,J＝7.8Hz,2H),7.69(t,J＝7.2Hz,1H),7.52(t,J＝7.8 Hz,2H),7.40(d,J＝7.2Hz,2H),7.37-7.34(m,2H),7.23(t,J＝7.2Hz, 1H),6.46(dd,J＝7.8,3.0Hz,1H),3.85(s,3H),3.82(dd,J＝14.4,7.8 Hz,1H),3.39(s,3H),2.94(dd,J＝14.4,3.0Hz,1H). 13 C NMR(150 MHz,CDCl 3 )δ167.6,167.2,166.1,156.1(d,J C-F ＝27.0Hz),148.1, 144.7,140.3(d,J C-F ＝238.5Hz),135.7,135.7,131.1,130.8,129.5,128.8, 126.8,124.5(d,J C-F ＝36.0Hz),120.5,82.6,53.7,53.0,46.4. 19 F NMR (565MHz,CDCl 3 )δ–162.77.HRMS(ESI):m/z calcd.for C 24 H 20 FN 3 O 8 Na + [M+Na] + :520.1127,found 520.1125.
3ca:Colorless oil；63％yield,88％ee.[α] D 20 ＝+65.0(c＝0.2,CH 2 Cl 2 ). R f ＝0.42(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL IF,n-hexane /2-propanol＝75/25,flow rate＝0.8mL/min,λ＝254nm,retention time:27.179min,30.949min. 1 H NMR(600MHz,CDCl 3 )δ7.93(d,J＝6.6 Hz,2H),7.88(s,1H),7.65(t,J＝7.2Hz,1H),7.50(t,J＝7.8Hz,2H), 7.40(d,J＝7.2Hz,2H),7.36-7.33(m,2H),7.21(t,J＝7.8Hz,1H),6.55 (dd,J＝7.8,3.0Hz,1H),3.83(s,3H),3.80(q,J＝7.2Hz,1H),3.40(s, 3H),2.94(dd,J＝14.4,3.0Hz,1H),2.41(q,J＝7.2Hz,2H),1.17(t,J＝ 7.8Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ169.1,167.8,166.3,162.6, 149.6,145.1,135.2,135.0,131.7,130.6,129.3,128.8,126.6,120.5,117.2,81.9,53.6,52.9,46.3,20.3,12.5.HRMS(ESI):m/z calcd.for C 26 H 25 N 3 O 8 Na + [M+Na] + :530.1534,found 530.1527.
3da:Colorless oil；47％yield,95％ee.[α] D 20 ＝+45.8(c＝0.3,CH 2 Cl 2 ). R f ＝0.39(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL IA, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:12.237min,14.395min. 1 H NMR(600MHz,CDCl 3 )δ 8.01(d,J＝8.4Hz,1H),7.95(d,J＝6.6Hz,2H),7.66(t,J＝6.6Hz,1H), 7.51(t,J＝8.4Hz,2H),7.40(d,J＝7.2Hz,2H),7.37-7.32(m,2H),7.21 (t,J＝7.2Hz,1H),6.46(dd,J＝7.8,3.0Hz,1H),5.88(d,J＝8.4Hz, 1H),3.84(s,3H),3.80(q,J＝7.2Hz,1H),3.39(s,3H),2.95(dd,J＝14.4, 3.0Hz,1H). 13 C NMR(150MHz,CDCl 3 )δ167.8,166.2,162.1,149.7, 144.9,139.8,135.4,131.5,130.7,129.4,128.8,126.6,120.3,102.8,82.5,53.7,53.0,46.7,29.8.HRMS(ESI):m/z calcd.for C 24 H 21 N 3 O 8 Na + [M+Na] + :502.1221,found 502.1216.
example 3:
according to the optimal reaction conditions in example 1, only the gram-scale raw materials and the substrate were changed for the reaction increase, and the gram-scale large-scale reaction results were as follows:
example 4:
[a]unless otherwise specified, the reaction conditions were 1a (0.05 mmol), 5a (x equiv), lewis acid (20 mol%), solvent (1.0 mL) under nitrogen for 24 hours [ b ]]Isolation yield [ c ]]Confirmation by chiral HPLC analysis [ d ]]Nd(OTf) 3 (30mol％). [e]Nd(OTf) 3 (40mol％).[f]Nd(OTf) 3 (50mol％).
In the reaction condition screening process, the influence of the catalyst, the catalyst dosage, the raw material ratio, the solvent and the temperature on the reaction is examined, and finally 40 percent of Nd (OTf) is determined 3 For the optimal catalyst, 5a was used in an amount of 6eq and 0 ℃ was the optimal reaction temperature, DCM was chosen as the optimal solvent.
Investigation of the reaction conditions:
chiral pyrimidine cyclopropane 1a (0.05 mmol,96% ee), enol silyl ether 5a (0.3 mmol,6.0 eq), nd (OTf) under nitrogen atmosphere 3 (40 mol%) and DCM (1.0, mL) were mixed and the reaction stirred at-20 ℃. TLC monitored the progress of the reaction, and water (1 mL) was added over night and the mixture was extracted with DCM (3 mL. Times.3). The organic phases were combined, na 2 SO 4 Drying and vacuum concentrating. The residue was purified by flash chromatography on silica gel (PE: ea=2:1) to give 43.0. 43.0 mg as a white product 6aa (64% yield and 96% ee); dr>20:1,96％ee.[α] D 20 ＝ -20.77(c＝0.2,CH 2 Cl 2 ).R f ＝0.57(Pet/EtOAc,2/1,v/v).m.p.:76.4-78.7 ℃.HPLC CHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝ 0.8mL/min,λ＝254nm,retention time:17.435min,21.203min. 1 H NMR(600MHz,CDCl 3 )δ8.00(s,1H),7.97-7.93(m,2H),7.83-7.79(m, 2H),7.66-7.62(m,1H),7.50(t,J＝7.8Hz,2H),7.34-7.28(m,3H),5.49-5.71(m,1H),3.76(s,3H),3.38(dd,J＝15.0,10.8Hz,1H),3.31(s, 3H),3.25(t,J＝12.0Hz,1H),2.58(q,J＝7.2Hz,1H),2.40(q,J＝7.2 Hz,1H),2.03(s,3H),0.99-0.96(m,12H),0.91-0.86(m,9H). 13 C NMR (150MHz,CDCl 3 )δ169.5,168.2,163.0,150.3,140.0,137.4,135.1, 131.8,130.8,129.2,128.6,128.3,127.5,111.6,88.5,70.4,58.5,52.9,52.5,51.9,43.7,38.7,18.5,18.29,18.26,13.9,13.0.HRMS(ESI):m/z calcd.for C 36 H 46 N 2 O 8 SiH + [M+H] + :663.3096,found 663.3096.
Example 5:
according to the optimal reaction conditions in example 4, only the reaction substrates were changed, and the reaction results were as follows:
typical compound characterization data are as follows:
6ab:Colorless oil；47％yield,dr>20:1,94％ee.[α] D 20 ＝-18.26(c＝1.1, CH 2 Cl 2 ).R f ＝0.59(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL ID, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:18.761min,22.496min. 1 H NMR(600MHz,CDCl 3 )δ 7.99-7.94(m,3H),7.82(q,J＝4.8Hz,2H),7.65(t,J＝7.2Hz,1H),7.50 (t,J＝7.8Hz,2H),7.01(t,J＝8.4Hz,2H),5.63-5.70(m,1H),3.76(s, 3H),3.41-3.36(m,4H),3.22(t,J＝12.0Hz,1H),2.56(dd,J＝12.6,7.2 Hz,1H),2.40(q,J＝7.2Hz,1H),2.04(s,3H),0.97-0.94(m,12H), 0.91-0.88(m,9H). 13 C NMR(150MHz,CDCl 3 )δ172.8,169.5,168.2, 162.9,162.8(d,J C–F ＝246.0Hz),150.3,137.3,136.0(d,J C–F ＝3.0Hz), 135.1,131.8,130.8,130.4(d,J C–F ＝7.5Hz),129.2,114.3(d,J C–F ＝19.5 Hz),111.7,87.9,70.3,53.0,52.6,51.8,43.8,38.6,18.28,18.25,13.8, 13.0. 19 F NMR(565MHz,CDCl 3 )δ–113.57.HRMS(ESI):m/z calcd. for C 36 H 45 FN 2 O 8 SiH + [M+H] + :681.3002,found 681.2996.
6ba:Colorless oil；43％yield,dr>20:1,83％ee.[α] D 20 ＝-29.42(c＝0.4, CH 2 Cl 2 ).R f ＝0.69(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL ID, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm, retention time:14.951min,18.161min. 1 H NMR(600MHz,CDCl 3 )δ 8.50(d,J＝6.6Hz,1H),7.96(q,J＝1.2Hz,2H),7.77-7.80(m,2H), 7.66-7.70(m,1H),7.53(t,J＝7.8Hz,2H),7.36-7.29(m,3H),5.74-5.66 (m,1H),3.75(s,3H),3.37(dd,J＝15.6,11.4Hz,1H),3.30(s,3H),3.19 (t,J＝12.6Hz,1H),2.60(q,J＝6.6Hz,1H),2.41(q,J＝6.6Hz,1H), 1.00-0.87(m,21H). 13 C NMR(150MHz,CDCl 3 )δ173.0,168.1,167.8, 156.2(d,J C–F ＝27.0Hz),148.9,140.5(d,J C–F ＝237.0Hz),139.6,135.6, 131.2,130.9,129.4,128.7,128.1,127.6,126.3,126.1(d,J C–F ＝33.0Hz), 88.6,70.4,53.1,52.52,52.49,43.7,38.6,18.32,18.30,13.9. 19 F NMR (565MHz,CDCl 3 )δ–162.18.HRMS(ESI):m/z calcd.for C 35 H 43 FN 2 O 8 Si Na + [M+Na] + :689.2665,found 689.2658.
6ca:Colorless oil；40％yield,dr>20:1,92％ee.[α] D 20 ＝-11.5(c＝1.1, CH 2 Cl 2 ).R f ＝0.63(Pet/EtOAc,2/1,v/v).HPLC CHIRALCEL ID, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm, retention time:14.247min,16.665min. 1 H NMR(600MHz,CDCl 3 )δ 7.99-7.94(m,3H),7.80(d,J＝7.8Hz,2H),7.64(t,J＝7.8Hz,1H),7.50 (t,J＝7.2Hz,2H),7.29-7.34(m,3H),5.66-5.73(m,1H),3.76(s,3H), 3.36-3.42(m,1H),3.32(s,3H),3.27(t,J＝12.6Hz,1H),2.60(q,J＝6.6 Hz,1H),2.40-2.48(m,3H),1.23(t,J＝7.8Hz,3H),0.96-1.00(m,12H),0.86-0.90(m,9H). 13 C NMR(150MHz,CDCl 3 )δ172.7,169.6,168.3, 162.7,150.2,140.0,136.7,135.0,131.9,130.8,130.6,129.21,129.18, 128.6,128.3,127.5,117.5,88.5,70.4,52.9,52.5,52.0,43.7,38.7,20.5,18.31,18.29,17.82,17.78,13.9,12.8,12.0.HRMS(ESI):m/z calcd.for C 37 H 48 N 2 O 8 SiK + [M+K] + :715.2812,found 715.2817.
example 6:
according to the optimal reaction conditions in example 4, only gram-scale raw materials and substrates were changed to increase the reaction, and the reaction results were as follows:
example 7:
under a nitrogen atmosphere, the chiral isoxazolopyrimidine nucleoside analog 3aa (0.1 mmol, 49.3mg,96% ee) and KOH (0.6 mg,10 mol%) were dissolved in methanol (1 mL) and stirred at room temperature for 6 hours. Quench with water (1 mL) and extract with DCM (5 mL. Times.3). The organic phases were combined, na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane: methanol=20:1) to give the desired product 8aa (35.0 mg,90% yield,95% ee). Colorless oil;90% yield,35.0mg,96% ee [ alpha ]] D 20 ＝+72.7(c＝1.0, CH 2 Cl 2 ).R f ＝0.28(CH 2 Cl 2 /CH 3 OH,2/1,v/v).HPLC CHIRALCEL IA, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm, retention time:11.280min,15.531min. 1 H NMR(600MHz,CDCl 3 )δ 8.76(s,1H),7.74(s,1H),7.38(dd,J＝9.0,1.2Hz,2H),7.35-7.31(m, 2H),7.19(t,J＝7.2Hz,1H),6.52(q,J＝3.6Hz,1H),3.80(s,3H),3.77 (dd,J＝13.8,7.2Hz,1H),3.41(s,3H),2.88(dd,J＝13.8,3.6Hz,1H), 1.94(s,3H). 13 C NMR(150MHz,CDCl 3 )δ167.8,166.4,163.8,150.7, 145.2,135.7,130.6,128.7,126.4,120.3,111.5,81.7,53.5,52.9,46.3,12.9.HRMS(ESI):m/z calcd.for C 21 H 22 N 2 O 7 Na + [M+Na] + :412.1115, found 412.1105.
Example 8:
under nitrogen, the chiral isoxazole pyrimidine nucleoside analog 3aa (0.1 mmol, 49.3mg,96% ee) was combined with NaBH 4 (22.8 mg,0.6 mmol) was dissolved in methanol (1 mL) and stirred at room temperature for 48 hours. Quench with water (1 mL) and extract with DCM (5 mL. Times.3). The organic phases were combined, na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane)Alkane: methanol=20:1) to give the desired product 9aa (10.1 mg,23% yield,92% ee). Colorless oil;23% yield,10.1mg,92% ee [ alpha ]] D 20 ＝+25.0(c＝0.1, CH 2 Cl 2 ).R f ＝0.26(CH 2 Cl 2 /CH 3 OH,20/1,v/v).HPLC CHIRALCEL IA, n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:7.150min,8.993min. 1 H NMR(600MHz,CDCl 3 )δ7.94 (d,J＝7.2Hz,2H),7.83(s,1H),7.81(s,1H),7.65(t,J＝7.2Hz,1H), 7.56-7.43(m,4H),7.39(d,J＝7.8Hz,2H),6.39(dd,J＝7.8,4.2Hz,1H), 3.91(s,2H),3.61-3.49(m,3H),3.14(dd,J＝14.4,7.8Hz,1H),2.80(dd, J＝14.4,4.2Hz,1H),2.22(t,J＝7.8Hz,1H),1.96(s,3H). 13 C NMR (100MHz,CDCl 3 )δ169.0,167.8,166.3,162.9,149.8,145.2,135.5, 131.8,130.7,129.3,128.8,126.5,120.4,111.5,82.1,53.6,52.9,46.4, 29.9,13.0.HRMS(ESI):m/z calcd.for C 23 H 23 N 3 O 6 Na + [M+Na] + : 460.1479,found 460.1477.
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are within the scope of the invention.
Claims (4)
1. A method for synthesizing a chiral isoxazole cyclic nucleoside analogue by cycloaddition, which is characterized by comprising the following steps: chiral pyrimidine cyclopropane 1 and nitrosoaromatic hydrocarbon 2 are used as raw materials, and react in an organic solvent under the action of a Lewis acid catalyst to obtain a chiral isoxazole carbocyclic nucleoside analogue 3; the reaction equation is as follows:
wherein R is 1 Selected from hydrogen, halogenA plain, C1-C4 alkyl; r is R 2 Halogen, nitrile group, nitro, trifluoromethyl and C1-C3 alkoxy ester group; the Lewis acid catalyst is selected from MgBr 2 Or MgI 2 。
2. The method for synthesizing the chiral isoxazole cyclic nucleoside analogue by cycloaddition according to claim 1, which is characterized in that: the molar ratio of chiral pyrimidine cyclopropane 1, nitrosoarene 2 and Lewis acid catalyst is 1:1-1.5:0.01-0.05.
3. The method for synthesizing the chiral isoxazole cyclic nucleoside analogue by cycloaddition according to claim 1, which is characterized in that: the organic solvent is selected from dichloromethane, toluene, fluorobenzene, chlorobenzene or 1, 2-dichloroethane; the reaction temperature is-20 ℃ to 40 ℃.
4. A method for synthesizing a chiral isoxazole cyclic nucleoside analog, comprising the steps of: obtaining chiral isoxazole cyclic nucleoside 3 by adopting any one of claims 1 to 3, and then reacting the chiral isoxazole cyclic nucleoside 3 in the presence of inorganic base to obtain a product 8, or reducing the chiral isoxazole cyclic nucleoside 3 under the action of sodium borohydride to obtain a product 9; the corresponding structures are as follows:
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