CN117447505A - Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid - Google Patents
Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid Download PDFInfo
- Publication number
- CN117447505A CN117447505A CN202311427301.8A CN202311427301A CN117447505A CN 117447505 A CN117447505 A CN 117447505A CN 202311427301 A CN202311427301 A CN 202311427301A CN 117447505 A CN117447505 A CN 117447505A
- Authority
- CN
- China
- Prior art keywords
- mmol
- carboxylic acid
- tert
- silicon
- butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 26
- 229910052710 silicon Inorganic materials 0.000 title claims description 22
- 239000010703 silicon Substances 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 15
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 15
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012298 atmosphere Substances 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 5
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 4
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims abstract description 3
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims abstract description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims abstract description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229940045803 cuprous chloride Drugs 0.000 claims abstract description 3
- 150000001282 organosilanes Chemical class 0.000 claims abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 3
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims abstract description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 30
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 28
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052786 argon Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- YTZKOQUCBOVLHL-UHFFFAOYSA-N p-methylisopropylbenzene Natural products CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 11
- 239000000377 silicon dioxide Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000001766 physiological effect Effects 0.000 abstract description 4
- 239000002585 base Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 238000007348 radical reaction Methods 0.000 abstract description 2
- 150000003254 radicals Chemical class 0.000 abstract description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 239000003208 petroleum Substances 0.000 description 24
- 238000012512 characterization method Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- OIKHZBFJHONJJB-UHFFFAOYSA-N dimethyl(phenyl)silicon Chemical compound C[Si](C)C1=CC=CC=C1 OIKHZBFJHONJJB-UHFFFAOYSA-N 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000007789 sealing Methods 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000003467 diminishing effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical class C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical class CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical class CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- -1 amide compound Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960002997 dehydrocholic acid Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical class C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical class C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical class FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical class OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical class O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical class C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000003961 organosilicon compounds Chemical class 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical class O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical class CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical group [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
- C07F7/0829—Hydrosilylation reactions
-
- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
A process for preparing the heterozygote of beta-silicon-base amide-carboxylic acid medicine includes such steps as preparing the mixture of beta-silicon-base amide-carboxylic acid medicineNThe carboxylic acid medicine with the arylsulfonyl acrylamide structure is prepared by heating and reacting substrate molecules with organosilane in the presence of a catalyst, a ligand, an additive, an oxidant and a solvent in an inert gas atmosphere in a pressure-resistant reaction tube for 12 hours, wherein the catalyst is cuprous iodide or cuprous chloride or cuprous bromide, the ligand is 2,2' -bipyridine or 4,4' -di-tert-butyl-2, 2' -bipyridine or 1, 10-phenanthroline, the additive is pyridine or 2, 6-lutidine or 2,4, 6-collidine or triethylenediamine, and the oxidant is di-tert-butyl peroxide or dicumyl peroxide or tert-butyl peroxybenzoate. The invention realizes important potential physiological activity through a free radical reaction strategyβ-first synthesis of silica-based amide-carboxylic acid drug hybrids.
Description
Technical Field
The present invention relates toβA method for synthesizing a silicon-based amide-carboxylic acid medicine hybrid, belonging to the technical field of chemistry.
Background
β-the silicon-based amide building blocks are widely present in drug molecules; the carboxylic acid medicine has important application in the fields of diminishing inflammation, resisting bacteria, relieving fever, easing pain, improving blood circulation, reducing blood sugar, resisting cancer, resisting oxidation, aging and the like. Silicon is the second largest element with the earth content being inferior to oxygen, the atomic radius of silicon is larger than that of carbon, the electronegativity is smaller than that of carbon, the lipophilicity is stronger than that of carbon, and the chemical characteristics of the silicon and the carbon are different, if silicon base is introduced into the existing medicine and bioactive molecule, the medicine effect is stronger, the selectivity is higher and the toxic and side effect is smallerIs substituted for the new medicine. In view of this, if one were toβThe introduction of the silylamide structure into the carboxylic acid molecules makes it possible to obtain compounds with novel physiological activities, which would provide a possible way for the creation of new drugs, however, no preparation is currently possibleβGeneral procedure for the hybrid of silicon-based amide-carboxylic acids.
Disclosure of Invention
The invention aims to provide a preparation method of a beta-silicon-based amide-carboxylic acid medicine hybrid.
In order to achieve the purpose of the invention, the following technical scheme is adopted: preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid, said methodβThe hybrid of the silicon-based amide-carboxylic acid medicines has a structure shown in a formula III and containsNThe carboxylic acid medicine with the arylsulfonyl acrylamide structure is prepared by heating and reacting substrate molecules with organosilane shown in a formula II in the presence of a catalyst, a ligand, an additive, an oxidant and a solvent in an inert gas atmosphere in a pressure-resistant reaction tube for 12 hours, and the conversion formula is as follows:
wherein: ar is aryl or heteroaryl, R is alkyl or aryl, R 1 Is alkyl or aryl, R 2 Is alkyl or aryl, R 3 Is alkyl or aryl, the catalyst is cuprous iodide or cuprous chloride or cuprous bromide, the ligand is 2,2' -bipyridine or 4,4' -di-tert-butyl-2, 2' -bipyridine or 1, 10-phenanthroline, the additive is pyridine or 2, 6-lutidine or 2,4, 6-trimethylpyridine or triethylene diamine, the oxidant is di-tert-butyl peroxide or dicumyl peroxide or tert-butyl peroxybenzoate, the inert gas atmosphere is argon or nitrogen, the solvent is tert-butyl alcohol or benzene or benzotrifluoride, and the reaction temperature is 100 to 140 o C。
The invention has the positive and beneficial technical effects that: is easily prepared fromNCarboxylic acid drugs with an arylsulfonyl acrylamide structure are taken as substrate molecules, cheap cuprous salt is taken as a catalyst, and important potential is realized through a free radical reaction strategyPhysiologically activeβ-first synthesis of silica-based amide-carboxylic acid drug hybrids.
Detailed Description
Examples of embodiments of the present invention are provided for more fully explaining the practice of the present invention, and are merely illustrative of the present invention and do not limit the scope of the present invention.
Implementation example 1:
sequentially adding into a pressure-resistant reaction tube with a stirrerNP-toluenesulfonylmethacrylamide modified probenecid (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-3:1β-silylamide-probenecid (compound 1) in 51% yield. Characterization data for compound 1 were: colorless oily matter, R f = 0.17 (10:1 petroleum ether / ethyl acetate); 68 mg, 51% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 8.28 (d,J= 8.5 Hz, 2H), 7.92 (d,J= 8.4 Hz, 2H), 7.44−7.41(m, 2H), 7.39−7.37 (m, 2H), 7.31−7.25 (m, 5H), 7.14 (d,J = 8.1 Hz, 2H), 7.09−7.07 (m, 2H), 6.84 (s, 1H), 3.12 (t,J= 7.6 Hz, 4H), 2.35 (s, 3H), 1.84 (d,J= 14.8 Hz, 1H), 1.71 (d,J = 14.8 Hz, 1H), 1.60−1.51 (m, 7H), 0.88 (t,J= 7.4 Hz, 6H), 0.14 (s, 6H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.2, 163.9, 146.4, 144.8, 141.6, 139.6, 137.1, 136.1, 133.4, 132.7, 130.7, 129.5, 128.7, 127.6, 127.1, 126.6, 121.7, 120.5, 50.0, 49.8, 27.9, 26.3, 21.9, 21.0, 11.1, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 38 H 46 N 2 NaO 5 SSi 693.2789; found 693.2798。
Implementation example 2:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified oxaprozin (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, and then heating to 130 ℃ on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-3:1βSilica-based amide-oxaprozin (compound 2) in 46% yield. Characterization data for compound 2 were: colorless oily matter, R f = 0.13 (10:1 petroleum ether / ethyl acetate); 62 mg, 46% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 7.67−7.65 (m, 2H), 7.60−7.58 (m, 2H), 7.45−7.42 (m, 2H), 7.40−7.29 (m, 11H), 7.27−7.25 (m, 2H), 7.14 (d,J = 8.1 Hz, 2H), 6.99−6.97 (m, 2H), 6.81 (s, 1H), 3.29 (t,J = 7.4 Hz, 2H), 3.14 (t,J= 7.4 Hz, 2H), 2.36 (s, 3H), 1.84 (d,J = 14.8 Hz, 1H), 1.72 (d,J = 14.8 Hz, 1H), 1.58 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ):δ 176.0, 170.7, 161.4, 146.5, 145.5, 141.7, 139.6, 137.0, 135.8, 135.1, 133.4, 132.3, 129.4, 128.9, 128.7, 128.6, 128.51, 128.46, 128.0, 127.8, 127.6, 126.6, 126.5, 121.7, 120.3, 50.0, 31.1, 27.9, 26.3, 23.4, 20.9, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 43 H 42 N 2 NaO 4 Si 701.2806; found 701.2810。
Implementation example 3:
sequentially adding into a pressure-resistant reaction tube with a stirrerNP-toluenesulfonylmethacrylamide modified ibuprofen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, then heating on an oil bathThe reaction was carried out at 130℃for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-5:1βSilica-based amide-ibuprofen (compound 3) in 46% yield. Characterization data for compound 3 were: colorless oily matter, R f = 0.44 (20:1 petroleum ether / ethyl acetate); 54 mg, 46% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 7.45−7.45 (m, 2H), 7.33−7.25 (m, 9H), 7.17−7.14 (m, 4H), 6.86 (d,J = 8.9 Hz, 2H), 6.82 (s, 1H), 3.92 (q,J= 7.1 Hz, 1H), 2.50 (d,J= 7.2 Hz, 2H), 2.37 (s, 3H), 1.94−1.88 (m, 1H), 1.86−1.83 (m, 1H), 1.72 (d,J = 14.8 Hz, 1H), 1.60 (d,J = 7.2 Hz, 3H), 1.58 (s, 3H), 0.94 (d,J= 6.6 Hz, 6H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.0, 173.3, 146.7, 141.7, 140.8, 139.61, 137.1, 137.0, 135.6, 133.4, 129.44, 129.43, 128.7, 127.6, 127.1, 126.6, 121.6, 120.3, 49.9, 45.1, 45.0, 30.1, 27.9, 26.3, 22.4, 20.9, 18.5, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 38 H 45 NNaO 3 Si 614.3061; found 614.3055。
Implementation example 4:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified naproxen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-5:1β-silylamide-naproxen (compound 4) in 70% yield. Characterization data for compound 4 are: colorless oily matter, R f = 0.28 (10:1 petroleum ether / ethyl acetate); 86 mg, 70% yield; 1 H NMR (400 MHz, CDCl 3 ): δ7.78-7.74 (m, 3H), 7.50 (dd,J = 8.5 Hz,J= 1.4 Hz, 1H), 7.45-7.43 (m, 2H), 7.33-7.25 (m, 7H), 7.20-7.13 (m, 4H), 6.88-6.86 (m, 2H), 6.80 (s, 1H), 4.09 (q,J= 7.1 Hz, 1H), 3.94 (s, 3H), 2.36 (s, 3H), 1.86 (d,J = 14.8 Hz, 1H), 1.73-1.69 (m, 4H), 1.57 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.0, 173.2, 157.7, 146.7, 141.7, 139.6, 137.0, 135.7, 135.1, 133.8, 133.4, 129.4, 129.3, 128.9, 128.7, 127.6, 127.3, 126.6, 126.08, 126.06, 121.6, 120.2, 119.1, 55.3, 50.0, 45.5, 27.9, 26.3, 20.9, 18.5, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 39 H 41 NNaO 4 Si 638.2697; found 638.2705。
Implementation example 5:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified gemfibrozil (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), displacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-10:1β-silylamide-gemfibrozil (compound 5) in 54% yield. Characterization data for compound 5 were: colorless oily matter, R f = 0.46 (20:1 petroleum ether / ethyl acetate); 69 mg, 54% yield; 1 H NMR (400 MHz, CDCl 3 ): d 7.45−7.43 (m, 2H), 7.38−7.30 (m, 5H), 7.28−7.25 (m, 2H), 7.10 (d,J = 8.0 Hz, 2H), 7.01 (d,J= 7.4 Hz, 1H), 6.91−6.89 (m, 2H), 6.81 (s, 1H), 6.68 (d,J= 7.5 Hz, 1H), 6.64 (s, 1H), 4.00−3.97 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H), 1.87−1.83 (m, 5H), 1.72 (d,J= 14.9 Hz, 1H), 1.58 (s, 3H), 1.36 (s, 6H), 0.16 (s, 3H) 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.4, 176.0, 156.8, 146.9, 141.7, 139.6, 137.0, 136.4, 135.6, 133.4, 130.3, 129.4, 128.7, 127.6, 126.6, 123.5, 121.7, 120.7, 120.3, 111.9, 67.7, 50.0, 42.3, 37.1, 27.9, 26.3, 25.2, 25.1, 21.4, 20.9, 15.8, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 40 H 49 NNaO 4 Si 658.3323; found 658.3335。
Implementation example 6:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified stearic acid (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), displacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-10:1βSilica-based amide-stearic acid (compound 6) in 53% yield. Characterization data for compound 6 were: colorless oily matter, R f = 0.58 (20:1 petroleum ether / ethyl acetate); 71 mg, 53% yield; 1 H NMR (400 MHz, CDCl 3 ): δ7.44-7.42 (m, 2H), 7.34-7.28 (m, 5H), 7.27-7.25 (m, 2H), 7.14 (d,J = 8.0 Hz, 2H), 6.96-6.94 (m,2H), 6.80 (s, 1H), 2.52 (t,J = 7.4 Hz, 2H), 2.36 (s, 3H), 1.84 (d,J= 14.8 Hz, 1H), 1.77-1.69 (m, 3H), 1.58 (s,3H), 1.41-1.28 (m, 28H), 0.90 (t,J = 6.7 Hz, 3H), 0.154 (s, 3H), 0.148 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.0, 172.4, 146.6, 141.7, 139.6, 137.0, 135.6, 133.4, 129.5, 128.7, 127.6, 126.6, 121.8, 120.3, 50.0, 34.3, 31.9, 29.7, 29.63, 29.56, 29.4, 29.3, 29.2, 29.1, 27.9, 26.3, 24.9, 22.7, 20.9, 14.1, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 43 H 63 NNaO 3 Si 692.4469; found 692.4480。
Implementation example 7:
sequentially adding into a pressure-resistant reaction tube with a stirrerNP-toluenesulfonylmethacrylamide modified fenbufen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-5:1βSilica-based amide-fenbufen (compound 7) was produced in 42%. Characterization data for compound 7 were: colorless oily matter, R f = 0.12 (10:1 petroleum ether / ethyl acetate); 54 mg, 42% yield; 1 H NMR (400 MHz, CDCl 3 ): d 8.09−8.07 (m, 2H), 7.72−7.70 (m, 2H), 7.66−7.64 (m, 2H), 7.51−7.47 (m, 2H), 7.45−7.40 (m, 3H), 7.34−7.26 (m, 7H), 7.15 (d,J = 8.0 Hz, 2H), 7.02−7.00 (m, 2H), 6.82 (s, 1H), 3.45 (t,J= 6.5 Hz, 2H), 3.01 (t,J = 6.5 Hz, 2H), 2.36 (s, 3H), 1.85 (d,J = 14.8 Hz, 1H), 1.72 (d,J= 14.8 Hz, 1H), 1.58 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 197.4, 176.1, 171.6, 146.6, 146.0, 141.7, 139.8, 139.6, 137.0, 135.7, 135.1, 133.4, 129.4, 128.9, 128.7, 128.6, 128.2, 127.6, 127.24, 127.23, 126.6, 121.8, 120.4, 50.0, 33.4, 28.4, 27.9, 26.3, 20.9, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 41 H 41 NNaO 4 Si 662.2697; found 662.2690。
Implementation example 8:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified flurbiprofen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, then in oilThe reaction was carried out with heating to 130℃in a bath for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-5:1βSilica-based amide-flurbiprofen (compound 8) in 61% yield. Characterization data for compound 8 were: colorless oily matter, R f = 0.32 (20:1 petroleum ether / ethyl acetate); 77 mg, 61% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 7.58 (d,J = 7.4 Hz, 2H),7.49−7.37 (m, 6H), 7.33−7.21 (m, 9H), 7.15 (d,J= 8.1 Hz, 2H), 6.92 (d,J= 8.9 Hz, 2H), 6.80 (s, 1H), 3.98 (q,J = 7.1 Hz, 1H), 2.36 (s, 3H), 1.84 (d,J = 14.8 Hz, 1H), 1.72 (d,J = 14.8 Hz, 1H), 1.65 (d,J = 7.2 Hz, 3H), 1.58 (s, 3H), 0.152 (s, 3H), 0.147 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ):δ 176.1, 172.5, 159.7 (d, 1 J C,F = 248.5 Hz), 146.6, 141.6, 141.2 (d, 3 J C,F = 8.0 Hz), 139.6, 137.0, 135.8, 135.4, 133.4, 131.0 (d, 3 J C,F = 4.0 Hz), 128.9 (d, 3 J C,F = 3.0 Hz), 128.7, 128.4, 127.70, 127.65, 126.6, 123.6, 123.5, 121.5, 120.3, 115.3 (d, 2 J C,F = 24.5 Hz), 50.0, 45.0, 27.9, 26.3, 20.9, 18.4, -1.4, -1.7; 19 F NMR (376 MHz, CDCl3): δ -117.30; HRMS (ESI) m/z: [M+Na] + Calcd for C 40 H 40 FNNaO 3 Si 652.2654; found 652.2663。
Implementation example 9:
sequentially adding into a pressure-resistant reaction tube with a stirrerNPara-toluenesulfonylmethacrylamide modified ketoprofen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), replacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction, the solvent was removed by rotary evaporator, and the resulting mixture was purified by column chromatography to give a developing solventThe petroleum ether/ethyl acetate mixed solution with the volume ratio of 20:1-5:1 is obtained as requiredβSilicon-based amide-ketoprofen (compound 9) in 54% yield. Characterization data for compound 9 were: colorless oily matter, R f = 0.23 (10:1 petroleum ether / ethyl acetate); 69 mg, 54% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 7.85−7.81 (m, 3H), 7.75−7.73 (m, 1H), 7.65−7.59 (m, 2H), 7.52−7.47 (m, 3H), 7.45−7.43 (m, 2H), 7.35−7.30 (m, 5H), 7.28−7.25 (m, 2H), 7.14 (d,J = 8.1 Hz, 2H), 6.91−6.88 (m, 2H), 6.83 (s, 1H), 4.03 (q,J= 7.2 Hz, 1H), 2.36 (s, 3H), 1.84 (d,J= 14.8 Hz, 1H), 1.72 (d,J= 14.8 Hz, 1H), 1.65 (d,J= 7.2 Hz, 3H), 1.58 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 196.4, 176.1, 172.6, 146.5, 141.7, 140.2, 139.6, 138.0, 137.4, 137.0, 135.8, 133.4, 132.5, 131.4, 130.0, 129.4, 129.21, 129.15, 128.73, 128.68, 128.3, 127.6, 126.6, 121.5, 120.3, 50.0, 45.4, 27.9, 26.3, 20.9, 18.5, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 41 H 41 NNaO 4 Si 662.2697; found 662.2707。
Implementation example 10:
sequentially adding into a pressure-resistant reaction tube with a stirrerNP-toluenesulfonylmethacrylamide modified febuxostat (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), displacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-3:1βSilica-based amide-febuxostat (compound 10) yield was 51%. Characterization data for compound 10 are: colorless oily matter, R f = 0.13 (10:1 petroleum ether / ethyl acetate); 72 mg, 51% yield; 1 H NMR (400 MHz, CDCl 3 ): δ 8.16 (d,J= 2.2 Hz, 1H), 8.11 (dd,J = 8.9 Hz,J = 2.3 Hz, 1H), 7.44−7.42 (m, 2H), 7.38−7.35 (m, 2H), 7.31−7.25 (m, 5H), 7.14 (d,J= 8.0 Hz, 2H), 7.08−7.05 (m, 2H), 7.02 (d,J= 9.0 Hz, 1H), 6.84 (s, 1H), 3.90 (d,J= 6.5 Hz, 2H), 2.80 (s, 3H), 2.35 (s, 3H), 2.25−2.16 (m, 1H), 1.84 (d,J= 14.8 Hz, 1H), 1.71 (d,J= 14.8 Hz, 1H), 1.57 (s, 3H), 1.09 (d,J = 6.7 Hz, 6H), 0.144 (s, 3H), 0.140 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 176.1, 168.1, 162.9, 162.6, 160.4, 146.1, 141.7, 139.6, 137.0, 136.1, 133.4, 132.6, 132.2, 129.5, 128.7, 127.6, 126.6, 125.8, 121.8, 120.5, 120.4, 115.3, 112.6, 103.0, 75.7, 50.0, 28.1, 27.9, 26.3, 20.9, 17.6, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 41 H 43 N 3 NaO 4 SSi 724.2636; found 724.2649。
Implementation example 11:
sequentially adding into a pressure-resistant reaction tube with a stirrerNP-toluenesulfonylmethacrylamide modified loxoprofen (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-tert-butyl peroxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-dimethylpyridine (0.2 mmol) and tert-butanol (1 mL), displacing argon and sealing the pressure-resistant reaction tube, and then heating to 130℃on an oil bath for reaction for 12 hours. After the reaction is finished, removing the solvent by using a rotary evaporator, purifying by using a column chromatography, and obtaining the required developing agent which is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1-5:1βSilica-based amide-loxoprofen (compound 11) was produced in 44%. Characterization data for compound 11 were: colorless oily matter, R f = 0.14 (10:1 petroleum ether / ethyl acetate); 56 mg, 44% yield; 1 H NMR (400 MHz, CDCl 3 ): δ7.46−7.43 (m, 2H), 7.34−7.25 (m, 9H), 7.20−7.14 (m, 4H), 6.88 (d,J= 8.9 Hz, 2H), 6.83 (s, 1H), 3.92 (q,J= 7.2 Hz, 1H), 3.17 (dd,J= 13.9 Hz,J= 4.0 Hz, 1H), 2.58−2.52 (m, 1H), 2.40−7.33 (m, 5H), 2.18−2.07 (m, 2H), 2.03−1.95 (m, 1H), 1.85 (d,J= 14.8 Hz, 1H), 1.79−1.70 (m, 2H), 1.60 (d,J= 7.2 Hz, 3H), 1.58 (s, 3H), 1.37−1.26 (m, 1H), 0.16 (s, 3H), 0.15 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 220.2, 176.0, 173.1, 146.7, 141.7, 139.6, 139.1, 137.8, 137.0, 135.6, 133.4, 129.4, 129.2, 128.7, 127.6, 127.5, 126.6, 121.5, 120.3, 50.9, 49.9, 45.1, 38.1, 35.2, 29.2, 27.9, 26.3, 20.9, 20.5, 18.5, -1.5, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 40 H 45 NNaO 4 Si 654.3010; found 654.3004。
Implementation example 12:
n-p-toluenesulfonylmethacrylamide modified dehydrocholic acid (0.2 mmol), dimethylphenylsilane (2.0 mmol), di-t-butylperoxide (1.0 mmol), cuprous iodide (0.04 mmol), 2' -bipyridine (0.04 mmol), 2, 6-lutidine (0.2 mmol) and t-butanol (1 mL) were sequentially added to a pressure-resistant reaction tube equipped with a stirrer, argon was substituted and the pressure-resistant reaction tube was sealed, and then heated on an oil bath to 130 oC for reaction for 12 hours. After the reaction, the solvent was removed by rotary evaporator, and purified by column chromatography, wherein the developing solvent was a mixed solution of petroleum ether/ethyl acetate in a volume ratio of 20:1-3:1, to obtain the desired beta-silylamide-dehydrocholic acid (compound 12) in 48% yield. Characterization data for compound 12 were: colorless oily matter, R f = 0.13 (2:1 petroleum ether / ethyl acetate); 76 mg, 48% yield; 1 H NMR (400 MHz, CDCl 3 ):δ 7.43-7.40 (m, 2H), 7.32−7.23 (m, 7H), 7.12 (d,J= 8.1 Hz, 2H), 6.95−6.92 (m, 2H), 6.79 (s, 1H), 2.94-2.81 (m, 3H), 2.64−2.57 (m, 1H), 2.51-2.43 (m, 1H), 2.38−2.26 (m, 7H), 2.24-2.19 (m, 2H), 2.16−2.10 (m, 2H), 2.08-2.00 (m, 3H), 1.99−1.93 (m, 2H), 1.89-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.56 (s, 3H), 1.51-1.46 (m, 1H), 1.40-1.33 (m, 5H), 1.30-1.25 (m, 1H), 1.08 (s, 3H), 0.90 (q,J = 6.8 Hz, 4H), 0.133 (s, 3H), 0.127 (s, 3H); 13 C NMR (100.6 MHz, CDCl 3 ): δ 211.9, 209.0, 208.7, 176.1, 172.6, 146.6, 141.7, 139.6, 137, 135.6, 133.4, 129.5, 128.7, 127.6, 126.6, 121.7, 120.4, 56.9, 51.7, 50.0, 48.9, 46.8, 45.6, 45.5, 44.9, 42.7, 38.6, 36.4, 36.0, 35.4, 35.2, 31.5, 30.3, 27.9, 27.6, 26.3, 25.1, 21.9, 20.9, 18.6, 11.8, -1.4, -1.7; HRMS (ESI) m/z: [M+Na] + Calcd for C 49 H 61 NNaO 6 Si 810.4160; found 810.4164。
The applicant adopts basically the same process conditions in 12 examples, the reaction time is 12 hours, and different products are prepared, so that the method has comparability, and the method is applicable to the preparation of the beta-silicon-based amide-carboxylic acid medicine hybrid.
Tables 1 and 2 below show the structures of the products corresponding to examples 1 to 12.
In the present invention, allNArylsulfonylacrylamide modified carboxylic acid drug molecules were synthesized according to literature (Organic Letters, 2023, 25, 5162-5167.).
Synthesized according to the inventionβThe silicon-based amide-carboxylic acid medicine hybrid has three important applications in the fields of organic chemistry, pharmaceutical chemistry and the like: firstly, it isβThe synthesis of the silicon-based amide compound provides a convenient way,βnot only are silicon-based amides an important class of organic synthesis intermediates useful in the construction of a wide variety of organosilicon compounds, but the structure is present in a wide variety of biologically active molecules,βclustered synthesis of silicon-based amides offers more possibilities for the discovery of bioactive molecules. Secondly, the method can be used for quickly constructing the quaternary carbon center, the quaternary carbon center has important influence on the spatial structure and the physiological activity of molecules, the construction of the quaternary carbon center is one of the most attractive fields in synthetic chemistry, and the method is provided for constructing the molecules containing the quaternary carbon center with high added value from low-cost and easily available olefin. Third, made by the patentβ-silicon basedAmide-carboxylic acid medicine hybrid is formed by fusing carboxylic acid medicine molecules and important substancesβThe silicon-based amide structure possibly has important physiological activities of relieving fever and pain, resisting bacteria and diminishing inflammation, improving blood circulation and the like, thereby providing a possible way for the creation of new drugs.
Claims (1)
1. Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid, said methodβThe hybrid of the silicon-based amide-carboxylic acid medicines has a structure shown in a formula III and containsNThe carboxylic acid medicine with the arylsulfonyl acrylamide structure is prepared by heating and reacting substrate molecules with organosilane shown in a formula II in the presence of a catalyst, a ligand, an additive, an oxidant and a solvent in an inert gas atmosphere in a pressure-resistant reaction tube for 12 hours, and the conversion formula is as follows:
wherein: ar is aryl or heteroaryl, R is alkyl or aryl, R 1 Is alkyl or aryl, R 2 Is alkyl or aryl, R 3 Is alkyl or aryl, the catalyst is cuprous iodide or cuprous chloride or cuprous bromide, the ligand is 2,2' -bipyridine or 4,4' -di-tert-butyl-2, 2' -bipyridine or 1, 10-phenanthroline, the additive is pyridine or 2, 6-lutidine or 2,4, 6-trimethylpyridine or triethylene diamine, the oxidant is di-tert-butyl peroxide or dicumyl peroxide or tert-butyl peroxybenzoate, the inert gas atmosphere is argon or nitrogen, the solvent is tert-butyl alcohol or benzene or benzotrifluoride, and the reaction temperature is 100 to 140 o C。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311427301.8A CN117447505A (en) | 2023-10-31 | 2023-10-31 | Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311427301.8A CN117447505A (en) | 2023-10-31 | 2023-10-31 | Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117447505A true CN117447505A (en) | 2024-01-26 |
Family
ID=89586920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311427301.8A Pending CN117447505A (en) | 2023-10-31 | 2023-10-31 | Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117447505A (en) |
-
2023
- 2023-10-31 CN CN202311427301.8A patent/CN117447505A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Maruoka et al. | Molecular recognition of ethers with modified organoaluminum reagents | |
| CN110156659B (en) | Preparation method of polyfluoro-substituted 3-hydroxyl oxindole compound | |
| CN117447505A (en) | Preparation method of beta-silicon-based amide-carboxylic acid medicine hybrid | |
| CN116514621B (en) | Method for constructing C-C bond at ortho-position of aryl by metal-catalyzed sulfur ylide and aryl sulfur/selenoacetic acid ester rearrangement reaction | |
| CN110204468B (en) | Asymmetric synthesis method of chiral alpha-thiocyano cyclic ketonic acid ester compound | |
| CN112321487A (en) | Polysubstituted isoindoline compound and preparation method thereof | |
| CN111269074A (en) | Preparation method of α -halogenated trifluoromethyl substituted alkane | |
| CN113336749B (en) | Preparation method of indoloquinoline compound | |
| CN111704587B (en) | Synthetic method of trifluoromethyl 1, 3-oxazine compound | |
| CN111662147B (en) | Process for preparing diynes and analogues thereof | |
| CN110724080B (en) | Synthetic method of aryl selenium cyanogen compound | |
| CN112279765B (en) | Preparation method of chiral alpha-fluoroketone compound | |
| CN109293575B (en) | Chiral monomer and preparation method thereof | |
| CN108658802B (en) | Chiral bi [ N, O ] cyclopalladated complex and synthetic method thereof | |
| CN113004109A (en) | Asymmetric synthesis method of chiral alpha-hydroxy-beta-ketonic acid ester compound | |
| CN115028568B (en) | Synthesis method of 3-selenoindole compound promoted by visible light | |
| CN114805069B (en) | Method for synthesizing alpha difluoro ester derivative from terminal olefin | |
| CN114605300B (en) | Synthesis method of aryl selenocyanate compound | |
| CN113845550B (en) | Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof | |
| Pellei et al. | Di-and tri-organotin (IV) complexes of the new bis (1-methyl-1H-imidazol-2-ylthio) acetate ligand and the decarboxylated analogues | |
| CN114149325A (en) | Method for preparing beta-methoxy fatty acid ester by using olefin and methyl formate promoted by visible light | |
| CN115583961A (en) | Synthetic method of alpha-quaternary carbon beta-silicon-based amide | |
| CN114702457A (en) | Green synthesis method of diarylmethylamine compound | |
| CN114292230A (en) | Palladium-catalyzed N-phenylpyridine-2-amine N-H carbonylation reaction taking DMF as methyl source | |
| CN116731059A (en) | Synthesis method of silicon-based substituted spiro [5,5] ketene compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |