CN113583036A - Preparation method of compound - Google Patents
Preparation method of compound Download PDFInfo
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- CN113583036A CN113583036A CN202110881055.8A CN202110881055A CN113583036A CN 113583036 A CN113583036 A CN 113583036A CN 202110881055 A CN202110881055 A CN 202110881055A CN 113583036 A CN113583036 A CN 113583036A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical group CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 claims abstract description 9
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012429 reaction media Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000003223 protective agent Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 description 2
- -1 4,4' -bismethoxytrityl Chemical group 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OBOHMJWDFPBPKD-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 OBOHMJWDFPBPKD-UHFFFAOYSA-N 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100170604 Mus musculus Dmap1 gene Proteins 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002699 waste material Substances 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
- C07F7/18—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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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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- 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 preparation method of a compound with a structure shown as a formula I, which comprises the following steps: (1) reacting a compound with a structure shown in a formula II with acrylonitrile to obtain a compound with a structure shown in a formula III; (2) reacting a compound with a structure shown in a formula III with bromopropylene to obtain a compound with a structure shown in a formula IV; (3) oxidizing a compound with a structure shown as a formula IV to obtain a compound with a structure shown as a formula V; (4) protecting a compound with a structure shown in a formula V through hydroxyl to obtain a compound with a structure shown in a formula VI; (5) reducing the compound with the structure shown in the formula VI to obtain the compound with the structure shown in the formula I.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of TEG linker.
Background
The TEG linker molecule is an important intermediate, but lacks an efficient synthesis method. The literature reports that the synthesis is carried out by taking triethylene glycol or pentaethylene glycol as raw materials, and the total yield is only about 5 percent through 6 steps of reaction (Jyoti Chattopanaya, Helvetica Chimica Acta,1999,82, 2186-F2200). WO 2007106907 discloses a similar synthesis method of short-chain linker, which takes acetone-condensed glycerol as raw material, and obtains the final product through 6 steps of reaction, but the atom economy is low.
Therefore, the synthesis method of the TEG linker has the advantages of short process route, convenient operation, low cost and practical value.
Disclosure of Invention
The invention aims to provide a preparation method of TEG linker.
The invention provides a preparation method of a compound with a structure shown as a formula I, which comprises the following steps:
(1) reacting a compound with a structure shown in a formula II with acrylonitrile to obtain a compound with a structure shown in a formula III;
(2) reacting a compound with a structure shown in a formula III with bromopropylene to obtain a compound with a structure shown in a formula IV;
(3) oxidizing a compound with a structure shown as a formula IV to obtain a compound with a structure shown as a formula V;
(4) protecting a compound with a structure shown in a formula V through hydroxyl to obtain a compound with a structure shown in a formula VI; and
(5) reducing the compound with the structure shown in the formula VI to obtain the compound with the structure shown in the formula I.
In another embodiment, the reaction temperature of step (1) is 0-30 ℃; preferably 20-25 deg.c.
In another embodiment, the mol ratio of the compound with the structure shown in the formula II in the step (1) to the acrylonitrile is 2.5-4: 1; preferably 3.0-3.5: 1.
In another embodiment, the reaction temperature of step (2) is 0-30 ℃; preferably 10-20 deg.C.
In another embodiment, the molar ratio of the compound having the structure shown in formula III, the bromopropene and the base in the step (2) is 1:1.1-2.0: 2.0-4.0; preferably 1:1.5-1.8: 2.5-3.0.
In another embodiment, the reaction solvent of step (3) is an aqueous organic solvent, the volume ratio of the organic solvent to water is 1: 0.5-2; preferably 1: 1-1.5.
In another embodiment, the organic solvent is selected from one or two or more of the following: acetone, ethanol, tetrahydrofuran, and acetonitrile; acetone and/or acetonitrile are preferred.
In another embodiment, the molar ratio of the compound with the structure shown in the formula IV in the step (3) to the oxidant is 1: 1-2; preferably 1: 1.2-1.5.
In another embodiment, step (3) is carried out at a pH of 10 to 12.
In another embodiment, the reaction temperature of step (4) is 0-25 ℃; preferably 5-10 deg.C.
In another embodiment, the reaction temperature of step (5) is 25-50 ℃; preferably 35-40 deg.C.
In another embodiment, Raney Ni (Raney Ni) is used as the catalyst in step (5).
In another embodiment, the weight ratio of the compound with the structure shown in the formula VI to the Raney nickel is 1: 0.05-0.2; preferably 1: 0.1-0.15.
In another embodiment, the compound with the structure shown in the formula IV obtained in the step (2) and the crude product of the compound with the structure shown in the formula VI obtained in the step (4) are directly used in the step (3) and the step (5) respectively.
Therefore, the synthesis method of the TEG linker has the advantages of short process route, convenience in operation, low cost and practical value.
Detailed Description
The inventor has conducted extensive and intensive studies and provides a preparation method of TEG linker which is low in cost, simple and convenient to operate and suitable for amplification.
The main compounds involved in the invention and their numbering:
wherein DMTr represents 4,4' -bismethoxytrityl, Tr represents triphenylmethyl, MMTr represents p-methoxytrityl, TBDMS represents tert-butyldimethylsilyl, TBDPS represents tert-butyldiphenylsilyl
As used herein, "compound having the structure shown in formula I" and "Compound 1" are used interchangeably and refer to the compounds having the structure shown in Table I or 1. And so on.
Specifically, the invention provides a preparation method of a compound with a structure shown as a formula I, which comprises the following steps:
firstly, mixing and reacting reaction liquid containing a compound with a structure shown in a formula II, a reaction solvent and acrylonitrile to obtain a compound with a structure shown in a formula III;
secondly, mixing and reacting reaction liquid containing a compound with a structure shown in a formula III, a reaction solvent and bromopropylene to obtain a compound with a structure shown in a formula IV;
thirdly, mixing and reacting reaction liquid containing a compound with a structure shown in a formula IV, a reaction solvent and an oxidant to obtain a compound with a structure shown in a formula V;
fourthly, mixing and reacting reaction liquid containing a compound with a structure shown in a formula V, a reaction solvent and a hydroxyl protective agent to obtain a compound with a structure shown in a formula VI;
and fifthly, mixing and reacting reaction liquid containing the compound with the structure shown in the formula VI, a reaction solvent and a catalyst to obtain the compound with the structure shown in the formula I.
The reaction solvent (reaction medium) used in the first step may include one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
The reaction in the first step is carried out at 0 to 30 ℃ and preferably at a reaction temperature of 20 to 25 ℃.
In one embodiment of the present invention, the molar ratio of the compound having the structure represented by formula II to acrylonitrile in the first step is 2.5-4:1, preferably 3.0-3.5: 1.
In one embodiment of the present invention, the first step is performed by column chromatography after obtaining a crude compound represented by formula iii, and the eluting solvent includes, but is not limited to, ethyl acetate/n-heptane from 1/10-1/5, dichloromethane/n-heptane from 1/20-1/5, and dichloromethane/ethanol from 1/100-1/20.
In one embodiment of the invention, in the first step, the compound with the structure shown in the formula II and a reaction solvent (reaction medium) are mixed and then added with an alkaline solution, and then acrylonitrile is added and mixed and reacted to obtain the compound with the structure shown in the formula III; the whole process is carried out at 0-30 deg.C (preferably 20-25 deg.C); the alkaline solution includes, but is not limited to, 25-35% sodium hydroxide solution, 25-35% potassium hydroxide solution, 25-35% sodium carbonate solution, 25-35% potassium carbonate solution, 25-35% cesium carbonate solution.
The reaction solvent (reaction medium) usable in the above-mentioned second step includes one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
The reaction in the above second step is carried out at 0 to 30 ℃ and preferably at 10 to 20 ℃.
In one embodiment of the present invention, the reaction solution of the second step further contains a base, which includes, but is not limited to, sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydroxide, potassium hydroxide; the molar ratio of the compound with the structure shown in the formula III, the bromopropylene and the alkali is 1:1.1-2.0:2.0-4.0, and preferably 1:1.5-1.8: 2.5-3.0.
In one embodiment of the present invention, the crude compound of formula IV obtained in the second step is not purified, but is directly used in the third step.
In one embodiment of the present invention, in the second step, the compound represented by the structural formula iii and the reaction solvent (reaction medium) are mixed, then the alkali is added at 8-12 ℃, then the bromopropylene is added and the reaction is carried out at 10-20 ℃ to obtain a crude product of the compound represented by the structural formula iv, and the crude product is directly used in the third step.
The reaction solvent (reaction medium) usable in the above third step is an aqueous organic solvent which may be one or more of acetone, ethanol, tetrahydrofuran and acetonitrile, preferably acetone or acetonitrile; the volume ratio of the organic solvent to the water is 1:0.5-2, preferably 1: 1-1.5.
The reaction in the above third step is carried out at 0 to 15 ℃ and preferably at 5 to 10 ℃.
Oxidizing agents which may be used in the third step include potassium permanganate, osmium tetroxide, iodine and wet silver carboxylates; in one embodiment of the invention, a potassium permanganate solution is used in a concentration of 1 to 5 w/w%, based on the total weight of the solution.
In one embodiment of the present invention, the molar ratio of the compound having the structure represented by formula IV to the oxidant in the third step is 1:1-2, preferably 1: 1.2-1.5.
In one embodiment of the present invention, the pH of the reaction solution in the third step is 10 to 12, preferably pH 12.
In one embodiment of the present invention, the above third step is performed by column chromatography after obtaining a crude compound represented by formula v, and the elution solvent includes, but is not limited to, methanol/dichloromethane of 1/150-1/80, ethanol/dichloromethane of 1/150-1/60, and acetone/dichloromethane of 1/100-1/50.
In an embodiment of the invention, in the third step, the crude product of the compound with the structure shown in the formula IV obtained in the second step is mixed with a water-containing organic solvent, the pH value is adjusted to 10-12, the temperature is controlled to 3-7 ℃, and then an oxidant is added to react at 5-10 ℃ to obtain the compound with the structure shown in the formula V.
The reaction solvent (reaction medium) used in the fourth step may include one or a mixture of two or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran and 2-methyltetrahydrofuran.
The reaction in the above fourth step is carried out at 0 to 25 ℃ and preferably at 5 to 10 ℃.
Examples of hydroxy protecting agents that may be used in the fourth step include, but are not limited to, DMTrCl, TrCl, MMTrCl, TBDMSCl, TBDPSCl.
In one embodiment of the present invention, the reaction solution in the fourth step further contains an acid-binding agent; the acid-binding agent is one or a mixture of more than two of pyridine, triethylamine and N, N-Diisopropylethylamine (DIPEA).
In one embodiment of the present invention, the molar ratio of the compound represented by the structural formula V in the fourth step, the hydroxyl protecting agent and the acid binding agent is 1:0.9-1.2:2.5-4, preferably 1:1.0-1.1: 3.0-3.5.
In one embodiment of the present invention, the crude compound of formula VI obtained in the fourth step is not purified, but directly used in the fifth step.
In an embodiment of the present invention, in the fourth step, the compound represented by the formula v and the reaction solvent (reaction medium) are mixed, then the acid-binding agent is added, the hydroxyl protecting agent is added in portions at 3-7 ℃, for example, but not limited to, 3-5 portions, each portion is separated by 20-30 minutes, and the like, and then the reaction is performed at 3-12 ℃, so as to obtain a crude product of the compound represented by the formula vi, which is directly used in the fifth step.
The reaction solvent (reaction medium) that can be used in the above-mentioned fifth step includes, but is not limited to, a mixed solvent of aqueous ammonia and ethanol, a mixed solvent of aqueous ammonia and methanol, a mixed solvent of aqueous ammonia and isopropanol; in one embodiment of the invention, the volume ratio of ammonia to alcohol is 1:1 to 3, preferably 1: 2.
The reaction in the above fifth step is carried out at 25 to 50 ℃ and preferably at 35 to 40 ℃.
Catalysts that may be used in the fifth step include, but are not limited to, Raney nickel (Raney Ni), palladium on carbon, preferably Raney nickel (Raney Ni). The fifth step uses hydrogen as a reducing agent.
In one embodiment of the present invention, the weight ratio of the compound having the structure represented by formula VI in the fifth step to the catalyst (Raney Ni) is 1:0.05-0.2, preferably 1: 0.1-0.15; the pressure of the reaction hydrogen is 0.3 to 1MPa, preferably 0.6 to 0.7 MPa.
In one embodiment of the present invention, the above-mentioned fifth step is performed with column chromatography after obtaining crude compound with structure shown in formula i, and elution solvents include, but are not limited to, methanol/dichloromethane of 1/50-1/20, acetone/dichloromethane of 1/50-1/10.
In one embodiment of the invention, the temperature during column chromatography is controlled to be about 10 +/-3 ℃.
In an embodiment of the present invention, in the fifth step, the crude compound having the structure shown in formula vi obtained in the fourth step, the reaction solvent (reaction medium) and the catalyst are mixed, and then replaced with nitrogen and hydrogen for 2 to 4 times, the hydrogen pressure is maintained at 0.3 to 1Mpa (preferably 0.6 to 0.7Mpa), and the reaction is performed at 25 to 50 ℃ (preferably 35 to 40 ℃) to obtain the compound having the structure shown in formula i.
In an embodiment of the present invention, Raney Ni (Raney Ni) is used as a catalyst in the fifth step, and is directly filter-pressed after the reaction is finished, the catalyst is in a filter cake, the filter cake can be recycled, and the product is concentrated, dried and purified in a filtrate to obtain the product. And other reduction methods have more waste solids or complicated post-treatment.
The theory or mechanism described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.
All features defined herein as numerical ranges or percentage ranges, such as values, amounts, levels and concentrations, are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to cover and specifically disclose all possible subranges and individual numerical values (including integers and fractions) within the range.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All features disclosed in this specification may be combined in any combination, provided that there is no conflict between such features and the combination, and all possible combinations are to be considered within the scope of the present specification. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are: the method provided by the invention has the advantages of few column chromatography steps, cheap raw materials, simple and convenient Raney Ni post-treatment for reducing the cyano group, cyclic utilization and suitability for industrial production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The units in weight volume percent in the present invention are well known to those skilled in the art and refer to, for example, the weight (g) of solute in 100 ml of solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Preparation of Compound 3
A2L reaction flask was charged with triethylene glycol (300g, 2mol, 3.5eq.) and tetrahydrofuran (1.5L), to which was added dropwise 30% sodium hydroxide solution (76.2g, 0.57mol, 1eq.) at 20-25 deg.C, and stirred at 20-25 deg.C for 1 hour. Acrylonitrile (30.2g, 0.57mol, 1eq.) was then added thereto. The reaction solution was stirred at 20-25 ℃ for 16 hours. After the reaction, the reaction solution was neutralized with 6N HCl, 1L of water was added, and extraction was performed 3 times with 1L of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the organic solvent removed by rotary evaporation under reduced pressure to give the crude product. The crude product was further purified by column chromatography to give 53.2g of compound 3 as a colorless oil in 45.95% molar yield.1H NMR(500MHz,DMSO-d6)δ(ppm):4.53(t,J＝6.3Hz,1H),3.45-3.63(m,12H),3.41(t,J＝6.5Hz,2H),2.71(t,J＝6.6Hz,2H)。
Example 2
Preparation of Compound 4
A500 mL reaction flask was charged with Compound 3(53.2g, 0.26 mol)1eq.) and tetrahydrofuran (260mL), cooling to about 10 deg.C, adding sodium hydride (31.2g, 0.78mol, 3eq.) in portions, and stirring at about 10 deg.C for 1 hour. Bromopropene (56.8g, 0.47mol, 1.8eq.) was then added thereto. The reaction solution was stirred at 10-20 ℃ for 6 hours. After completion of the reaction, 200mL of water was slowly dropped into the reaction mixture. And extracted 3 more times with 200mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and the organic solvent was removed by rotary evaporation under reduced pressure to give 66g of compound 4 as a crude product. The crude product was used in the next step without purification. Mass spectrum: MS (ESI) M/z 244.2(M + H)+)。
Example 3
Preparation of Compound 5
A3L reaction flask was charged with the crude product of Compound 4 (66g, 0.26mol, 1eq.), acetone (160mL) and water (160mL), and a small amount of sodium hydroxide was added to adjust the pH of the solution to about 12 and the temperature was reduced to about 5 ℃.
A2.5% aqueous solution of potassium permanganate (1972g, 0.31mol, 1.2eq.) was added dropwise thereto. After the addition, the reaction was continued at 5-10 ℃ with stirring for 1 hour. After the reaction was completed, the resulting solid was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure and then taken up with anhydrous ethanol (1L) twice to obtain a crude product. The crude product was further purified by column chromatography to give 36.9g of compound 5 as a pale yellow oil in 51.24% molar yield.1H NMR(500MHz,DMSO-d6)δ(ppm):4.60(d,J＝4.5Hz,1H),4.46(t,J＝6.6Hz,1H),3.64(t,J＝6.6Hz,2H),3.27-3.57(m,17H),2.67(t,J＝6.5Hz,2H)。
Example 4
Preparation of Compound 6
Compound 5(36.9g, 0.13mol, 1eq.) and dichloromethane (370mL) were added to a 500mL reaction flask, the mixture was dissolved with stirring at room temperature, pyridine (31.5g, 0.4mol, 3eq.) was added, the temperature was reduced to about 5 ℃, DMTrCl (49.6g, 0.15mol, and the average addition was divided into four times, with 20 to 30 minutes intervals each time) was added to the reaction solution. After the addition, the reaction was continued at 5-10 ℃ with stirring for 3 hours. After completion of the reaction, ethanol (50mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then washed successively with a saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and the organic solvent removed by rotary evaporation under reduced pressure to give 79.2g of an orange colorCrude product of compound 6. The crude product was used in the next step without purification. Mass spectrum: MS (ESI) M/z 580.3(M + H)+)。
Example 5
Preparation of Compound 6
Compound 5(36.9g, 0.13mol, 1eq.) and dichloromethane (370mL) were added to a 500mL reaction flask, dissolved with stirring at room temperature, imidazole (14.16g, 0.21mol, 1.6eq.) was added, and TBDMSCl (29.39g, 0.195mol, 1.5eq.) was added to the reaction solution. After the addition was complete, the reaction was stirred for a further 6 hours at 25 ℃. After completion of the reaction, the reaction mixture was quenched by adding water (300 mL). The mixture was allowed to stand for separation, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and the organic solvent was removed by rotary evaporation under reduced pressure to give 55g of a crude product of pale yellow compound 6. The crude product was used in the next step without purification. Mass spectrum: MS (ESI) M/z 392.3(M + H)+)。
Example 6
Preparation of Compound 1
A1L autoclave was charged with the crude product of Compound 6 (79.2g, 0.13mol, 1eq.), ethanol (300mL), ammonia (150mL) and Raney Ni (8g), and the mixture was subjected to nitrogen substitution 3 times and hydrogen substitution 3 times, then the pressure of hydrogen was maintained at 0.6MPa, and the temperature was raised to 35-40 ℃ for reaction for 6 hours. After the reaction was complete, the reaction mixture was filter-pressed and the filter cake was rinsed with ethanol (30 mL). The filtrate and the leacheate were combined, the filtrate was concentrated to dryness under reduced pressure, and then taken up twice with anhydrous ethanol (200mL) to obtain a crude product. The crude product was further purified by column chromatography to give 71.6g of compound 1 as a pale yellow oil in 92.3% molar yield.1H NMR(500MHz,DMSO-d6)δ(ppm):7.42(d,J＝7.5Hz,2H),7.26-7.32(m,6H),7.22(t,J＝7.5Hz,1H),6.89(d,J＝9.0Hz,4H),3.76-3.79(m,1H),3.74(s,6H),3.35-3.49(m,19H),2.95(d,J＝5.5Hz,2H),2.57(t,J＝7.0Hz,2H),1.53-1.58(m,2H)。
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (14)
1. A method for preparing a compound having a structure represented by formula i, comprising the steps of:
(1) reacting a compound with a structure shown in a formula II with acrylonitrile to obtain a compound with a structure shown in a formula III;
(2) reacting a compound with a structure shown in a formula III with bromopropylene to obtain a compound with a structure shown in a formula IV;
(3) oxidizing a compound with a structure shown as a formula IV to obtain a compound with a structure shown as a formula V;
(4) protecting a compound with a structure shown in a formula V through hydroxyl to obtain a compound with a structure shown in a formula VI;
(5) reducing the compound with the structure shown in the formula VI to obtain the compound with the structure shown in the formula I.
2. The method according to claim 1, wherein the reaction temperature in step (1) is 0 to 30 ℃; preferably 20-25 deg.c.
3. The preparation method according to claim 1, wherein the molar ratio of the compound having the structure shown in formula II to acrylonitrile in step (1) is 2.5-4: 1; preferably 3.0-3.5: 1.
4. The method according to claim 1, wherein the reaction temperature in the step (2) is 0 to 30 ℃; preferably 10-20 deg.C.
5. The preparation method according to claim 1, wherein the molar ratio of the compound having the structure represented by the formula III, bromopropene and the base in the step (2) is 1:1.1-2.0: 2.0-4.0; preferably 1:1.5-1.8: 2.5-3.0.
6. The method according to claim 1, wherein the reaction solvent of step (3) is an aqueous organic solvent, and the volume ratio of the organic solvent to water is 1: 0.5-2; preferably 1: 1-1.5.
7. The method according to claim 6, wherein the organic solvent is one or more selected from the group consisting of: acetone, ethanol, tetrahydrofuran, and acetonitrile; preferably acetone and/or acetonitrile.
8. The preparation method according to claim 1, wherein the molar ratio of the compound having the structure shown in formula IV to the oxidant in step (3) is 1: 1-2; preferably 1: 1.2-1.5.
9. The method according to claim 1, wherein the step (3) is carried out at a pH of 10 to 12.
10. The method according to claim 1, wherein the reaction temperature in the step (4) is 0 to 25 ℃; preferably 5-10 deg.C.
11. The method according to claim 1, wherein the reaction temperature in the step (5) is 25 to 50 ℃; preferably 35-40 deg.C.
12. The method according to claim 1, wherein Raney nickel (Raney Ni) is used as the catalyst in the step (5).
13. The preparation method according to claim 12, wherein the weight ratio of the compound represented by the structural formula VI to the Raney nickel is 1: 0.05-0.2; preferably 1: 0.1-0.15.
14. The process according to any one of claims 1 to 13, wherein the crude product of the compound of formula IV obtained in step (2) and the crude product of the compound of formula VI obtained in step (4) are used directly in step (3) and step (5), respectively.
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