WO2020073657A1 - Carbohydrate monophosphines, preparation method therefor and use thereof - Google Patents

Carbohydrate monophosphines, preparation method therefor and use thereof Download PDF

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WO2020073657A1
WO2020073657A1 PCT/CN2019/088461 CN2019088461W WO2020073657A1 WO 2020073657 A1 WO2020073657 A1 WO 2020073657A1 CN 2019088461 W CN2019088461 W CN 2019088461W WO 2020073657 A1 WO2020073657 A1 WO 2020073657A1
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methyl
carbohydrate
oxo
solution
phenyl
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施继成
张力学
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东莞市均成高新材料有限公司
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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Definitions

  • the present invention relates to novel chiral monophosphine ligands with azulose or idylpyranose units, including P-chiral monophosphine ligands, their preparation methods, and their coordinated transition metal complexes Compounds, and the use of catalytic systems composed of them and transition metals in catalyzing organic reactions, especially in the formation of CC, CN, and CO bonds.
  • transition metal complex catalysts A variety of organic reactions can be efficiently catalyzed by transition metal complexes, so transition metal complex catalysts often play an important role in the preparation of drugs and organic materials.
  • the performance of the transition metal complex catalyst essentially depends on the metal element itself, but it can efficiently realize a variety of organic conversions, including asymmetric catalytic conversion, and the contribution of the surrounding ligands to the regulation of the nature of the metal center.
  • organic ligands especially organic phosphine ligands, play an important role in the electronic properties of the metal center and the regulation of the three-dimensional environment around the metal center.
  • the ability of the coordination atom to donate electrons and accept feedback electrons regulates the electronic properties of the metal center and affects the coordination of other ligands to the metal center.
  • the radius of the coordination atom and the peripheral size it occupies will affect the metal center.
  • carbohydrate monophosphine (methyl 4,6-oxo-benzylidene-3-deoxy- ⁇ - D-Aranopyranoside-3) -diphenylphosphine has better catalytic performance in palladium-catalyzed Suzuki coupling reaction of brominated aromatic hydrocarbons, but it has better performance in catalyzing substrates such as chlorinated aromatic hydrocarbons Poor, the possible reason is that the phosphorus atom of this ligand has two phenyl groups with weak electron donating ability.
  • the phosphine ligands with carbohydrate units are obviously different from the skeleton structure of the above-mentioned representative phosphine ligands such as biphenyl, ferrocene, adamantyl and cyclopropyl, if they are connected to pyran
  • the substitution of the phosphorus atom on the dextrose skeleton is replaced by other substituents or the phosphorus atom is attached to other kinds of carbohydrate skeletons, so that phosphine ligands with novel structure and performance can be developed to enrich and satisfy the transition metal Catalytic system requirements for specific phosphine ligands.
  • the invention relates to: (1) carbohydrate monophosphine; (2) borane adduct, oxide, sulfide and selenide of carbohydrate monophosphine; (3) preparation method of carbohydrate monophosphine; (4) carbohydrate Palladium complex with compound monophosphine coordination; (5) Catalytic system composed of carbohydrate monophosphine and transition metal; (6) Catalytic system composed of palladium complex with carbohydrate monophosphine, or coordination of carbohydrate monophosphine Of palladium complex in catalyzing the coupling reaction of (pseudo) halogenated aromatic hydrocarbon as substrate.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations:
  • the carbohydrate unit may be an ⁇ -D-aradanose, ⁇ -D-aradanose, ⁇ -D-iduran or ⁇ -D-idulan unit;
  • R 1 is selected from H, (C1-C6) alkyl, (C6-C10) aryl or -CH 2 (C6-C10) aryl methylene, here (C6-C10) aryl and -CH 2 (C6 -C10) arylmethylene may have 1 to 3 substituents independently selected from nitro, (C1-C6) alkyl or -O (C1-C6) alkoxy;
  • R 4 and R 5 are each independently selected from H, OH, SH, (C1-C8) alkyl, (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aromatic Group, (C4-C20) heteroaryl, ferrocenyl or R 4 and R 5 are combined as 9-phosphafluorenyl, but one of R 4 and R 5 is selected from H, OH or SH, the other R 4 Or R 5 can not be H, OH or SH, here (C3-C10) cycloalkyl, (5-6 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl , Ferrocenyl, -CH 2 (C6-C10) arylmethylene and 9-phosphafluorenyl can have 1 to 3 independently selected from (C1-C6) alkyl (may have F atoms), -O (C1-C6) alkoxy
  • R 6 is selected from H, (C1-C6) alkyl, (C1-C8) acyl, -CH 2 (C6-C10) arylmethylene or R 9 SO 2 sulfonyl, where R 9 is selected from (C1- C6) alkyl or (C6-C10) aryl;
  • the carbohydrate unit is methyl (3-deoxy-4,6-oxo-benzylidene- ⁇ -D-pyran azreosidino-3-): 1) and R 4 and R 5 are both benzene when the group, R 6 is not H or methyl; 2) and R 4 is phenyl while R 5 is a methyl group, R 6 is not H or methyl; 3) and R 4 is phenyl while R When 5 is H, R 6 is not H.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 1 is (C1-C6) alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl, carbohydrate unit, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 1 is (C6-C10) aryl, it may be selected from phenyl, p-tolyl, p-nitrophenyl, p-methoxyphenyl or naphthyl, carbohydrate unit, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 1 is CH 2 (C6-C10) aryl methylene, it can be selected from phenyl methylene, p-tolyl methylene, p-methoxy phenyl methylene or naphthyl methylene, carbohydrate Units, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 2 or R 3 is (C1-C6) alkyl, it may be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl, carbohydrate unit, R 1 , R 4 , R 5 , R 6 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 2 or R 3 is -CH 2 (C6-C10) aryl methylene, it may be selected from benzylidene, p-toluene methylene, p-methoxybenzylidene or naphthalene methylene, Carbohydrate units, R 1 , R 4 , R 5 , R 6 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 2 or R 3 is (C1-C8) acyl, it may be selected from formyl, acetyl, propionyl, benzoyl or phenylacetyl, carbohydrate unit, R 1 , R 4 , R 5 , R 6 and R
  • the definition of 9 is the same as the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 4 and R 5 can not both be H, OH, and SH, both R a is selected from H 4 and R 5 are, when the OH or SH, the other of R 4 and R 5 can not be selected from H, OH or SH, It can only be selected from the rest of the definition of R 4 and R 5 in the first aspect.
  • the definitions of carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are the same as those in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein
  • R 4 or R 5 is (C1-C8) alkyl, it can be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tert-amyl or tert-butyl Octyl, carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 4 or R 5 is (C3-C10) cycloalkyl, each may be independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, carbohydrate unit
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 4 or R 5 is (C6-C20) aryl
  • it can be selected from phenyl, 4-tolyl, 2-tolyl, 2- (dimethylamino) phenyl, 4- (dimethylamino) phenyl , 2-methoxyphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-bistrifluoromethylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-bis (dimethylamino) phenyl, 3,4,5-trimethoxyphenyl, 2-biphenyl Group,
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 4 or R 5 is (C4-C20) heteroaryl, it can be selected from 2-furyl, 2-thienyl, 5-methyl 2-furyl, 5-methyl-2-thienyl, 2- Pyridyl, 3-pyridyl or 8-quinolinyl, carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 4 or R 5 is ferrocenyl, it can be selected from ferrocenyl, acetylferrocenyl or (1-dimethylamino-ethyl) ferrocenyl-2-, carbohydrate unit, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 6 is (C1-C6) alkyl, it can be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4.
  • R 5 , R 7 , R 8 and R 9 are the same as the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 6 is -CH 2 (C6-C10) aryl methylene, benzyl methylene, 4-methoxybenzylidene or naphthalene methylene
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 6 is (C1-C8) acyl, it may be selected from formyl, acetyl, propionyl, benzoyl or phenylacetyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4 , R 5 ,
  • R 7 , R 8 and R 9 are the same as the first aspect.
  • the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations,
  • R 6 is R 9 SO 2 sulfonyl, it can be selected from methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are as defined in the first aspect.
  • the present invention provides borane adducts of carbohydrate monophosphines, which have the general formula Va, Vb, VIa or VIb, and may also be a mixture of Va and Vb or a mixture of VIa and VIb except R 4 or R 5 is not OH or SH, other parts defined by R 4 and R 5 and carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are defined and defined in the same way first.
  • the present invention provides oxides, sulfides, or selenides of carbohydrate monophosphines, which have the general formula VIIa, VIIb, VIIIa, or VIIIb, and may also be a mixture of VIIa and VIIb or VIIIa and VIIIb Mixture, except that R 4 or R 5 are not H, OH or SH, the rest of R 4 and R 5 are defined as well as carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R The definition of 9 is the same as the first aspect.
  • the present invention provides the above-described carbohydrate monophosphines (general formula Ia, Ib or mixtures thereof, or IIa, IIb or mixtures thereof) and borane adducts (general formula Va , Vb or mixtures thereof, or VIa, VIb or mixtures thereof).
  • these carbohydrate monophosphines and their borane adducts can be prepared by the route described in Scheme 1, where the general formula IX contains 2,3-anhydride- ⁇ -D-mannopyranoside, 2,3- Anhydride- ⁇ -D-pyranoside, 2,3-anhydride- ⁇ -D-pyrantaloside, and 2,3-anhydride- ⁇ -D-pyrantaloside Carbohydrate epoxides, where R 1 , R 2 , and R 3 are as defined in the first aspect, and the general formula X may include 2,3-anhydride- ⁇ -D-allopyranoside, 2,3 -Anhydride- ⁇ -D-pyranoglucoside, 2,3-anhydride- ⁇ -D-glucopyranoside, and 2,3-anhydride- ⁇ -D-glucopyranoside
  • R 1 , R 2 and R 3 are the same as the first
  • an epoxide having the general formula IX or general formula X and HPR 4 R 5 at a temperature of -20 ° C to 150 ° C, respectively for the reaction in the range, the reaction temperature is preferably 0 ° C to 100 ° C, and a carbohydrate monophosphine is prepared, in which case R 6 is H and R 4 and R 5 are not OH or SH.
  • R 6 is (C1-C6) alkyl, -CH 2 (C6-C10) aryl methylene, (C1-C8) acyl or R 9 SO 2 can be further obtained by known secondary alcohol etherification or esterification Sulfonyl, where R 9 is selected from (C1-C6) alkyl or (C6-C10) aryl, a carbohydrate monophosphine.
  • the carbohydrate monophosphine described in the last paragraph is reacted with an adduct of 1 to 5 equivalents of borane BH 3 in tetrahydrofuran or dimethyl sulfide in a temperature range of -40 ° C to 60 ° C, preferably 1.1 to 2.0
  • the equivalent weight and the preferred reaction temperature are -10 ° C to 40 ° C, and a carbohydrate monophosphine borane adduct can be obtained, in which case R 4 and R 5 are not OH or SH.
  • carbohydrate monophosphine (the general formula is Ia, Ib or their mixture and IIa, IIb or their mixture), when one of R 4 or R 5 is H, it can be oxidized by O 2 or S 8 to the corresponding Secondary phosphine oxide or secondary phosphine sulfide with carbohydrate units.
  • carbohydrate monophosphines (general formula Ia, Ib or their mixtures and IIa, IIb or their mixtures), when neither R 4 or R 5 is H, OH or SH, they are tertiary phosphines It can be oxidized by O 2 , S 8 or Se to corresponding tertiary phosphine oxides, sulfides or selenides with carbohydrate units of general formula VII and VIII.
  • Carbohydrate monophosphine and its borane adduct or phosphine oxide, sulfide or selenide can be separated and purified by recrystallization or ordinary silica gel column chromatography to obtain the general formula Ia, Ib with optical purity ⁇ 95% , IIa and IIb carbohydrate monophosphines, or borane adducts of general formula IIIa, IIIb, IVa and IVb carbohydrate monophosphines with optical purity ⁇ 95%, or general formula VIIa with optical purity ⁇ 95% , VIIb, VIIIa and VIIIb carbohydrate monophosphine oxides, sulfides or selenides.
  • the compounds described herein with an optical purity of ⁇ 95% can also be obtained by (preparative) HPLC, and the chromatographic column used here can be chiral or achiral.
  • the present invention provides a method for deboration of the above-described carbohydrate monophosphine borane adduct (the general formula is Va, Vb or a mixture thereof and VIa, VIb or a mixture thereof).
  • DABCO triethylenediamine
  • the present invention provides a carbohydrate monophosphine as a transition metal complex or transition supporting a ligand and an element of Group VIII of the periodic table, such as palladium, nickel, platinum, rhodium, iridium, ruthenium, or cobalt
  • an element of Group VIII of the periodic table such as palladium, nickel, platinum, rhodium, iridium, ruthenium, or cobalt
  • the combination of metal salts is used as a catalyst.
  • the carbohydrate monophosphine provided by the present invention can be added to a suitable transition metal precursor to generate an active catalytic system in situ.
  • the present invention provides a series of carbohydrate monophosphine coordinated palladium complexes having the general formula XI, XII, XIII, XIV or XV:
  • L is a carbohydrate monophosphine as defined above;
  • X 3 and X 7 are independently selected from Cl, Br or I;
  • X 4 , X 5 and X 6 can be independently selected from Cl, Br, I, mesylate, Benzenesulfonate, p-toluenesulfonate, formate, acetate or benzoate;
  • R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from H, methyl or phenyl.
  • the present invention further provides the use of a palladium catalyst system and a palladium complex generated in situ to catalyze Suzuki-Miyaura coupling and Buchwald-Hartwig amination reaction.
  • a palladium catalyst system and a palladium complex generated in situ to catalyze Suzuki-Miyaura coupling and Buchwald-Hartwig amination reaction.
  • other transition metal catalyzed reactions that are obvious to those skilled in the art, especially Negishi coupling, Kumada coupling, Sonagashira alkynylation and Heck coupling, can also use the catalytic system provided by the present invention.
  • palladium salts or complexes that can generate a palladium catalyst in situ with the phosphine of the present invention, including palladium acetate, palladium chloride, acetylacetone palladium, diphenylmethyleneacetone palladium, tetrakis (triphenylphosphine) palladium , Diacetonitrile palladium chloride, dibenzonitrile palladium chloride, allyl palladium chloride dimer, crotonyl palladium chloride dimer, phenylpropenyl palladium chloride dimer, 2-aminobiphenyl-2 -Palladium chloride, 1,5-cyclooctadiene palladium chloride, or other sources of palladium well known to those skilled in the art.
  • the use of palladium complexes with phosphine coordination of carbohydrate units as the precursor of the catalyst is more advantageous for catalytic reaction applications, and in some cases will shorten the catalytic induction period.
  • the amount of the palladium complex of the present invention relative to the substrate halogenated aromatic hydrocarbon ratio may be 0.000001 to 0.1 equivalents. Based on the cost of the catalyst and the reliability of the reaction, the amount of palladium is more suitably selected in the range of 0.0001 To 0.02 equivalent.
  • an additional 0.5 to 50 times the carbohydrate-carrying monophosphine ligand according to the present invention is added in addition to palladium, which generally increases the life of the catalytic system or reduces the palladium
  • the amount used, the amount of additional ligand added is more in the range of 0.5 to 10 times.
  • the amount of palladium can be 0.000001 to 0.1 equivalent, and a more suitable range is selected from 0.00001 to 0.02 equivalent.
  • the amount ratio of phosphine ligand to palladium substance can range from 100: 1 to 1: 1, and the general range is from 10: 1 to 1: 1.
  • palladium salts or complexes and phosphine ligands with carbohydrate units can It is added to the reaction system independently in turn, or it may be that the palladium salt or complex and the phosphine ligand with carbohydrate unit are stirred and reacted in the solvent to form a palladium catalytic system solution, and then added to the reaction system.
  • the phosphine borane adduct with carbohydrate unit of the present invention needs to deprotect the borane before it can coordinate with palladium.
  • the phosphine ligand after deboration can be further purified by a short silica gel column or crystallization.
  • the purity of the phosphine ligand obtained by the deborane method of the present invention is sufficiently high without purification by a short silica gel column or crystallization. It can be directly used in the preparation of catalytic systems, which is also one of the characteristics of the present invention. Therefore, the carbohydrate unit phosphine borane adduct of the present invention has the advantages of convenient storage and convenient use.
  • the phosphine ligand of the present invention has good thermal stability under an inert atmosphere, and therefore can use the catalytic system provided by the present invention at a temperature as high as 200 ° C or higher. It is preferable that the reaction temperature is 0 ° C to 180 ° C, or even 20 ° C to 140 ° C to carry out the catalytic reaction.
  • the phosphine of the present invention can also be used under pressurization, usually the pressure can be up to 100 atmospheres, but it is preferred to carry out the reaction in the range of no more than 60 atmospheres to normal pressure.
  • phosphine of the present invention is a phosphorus atom connected to the 2- or 3-position of carbohydrates These are secondary carbon atoms, so these phosphines can be electron-rich and have a large steric hindrance, which is a popular feature for palladium-catalyzed coupling reactions.
  • the present invention provides multiple series of phosphine ligands having a variety of phosphine ligands with different electronic properties and stereo properties, which is extremely advantageous for satisfying the needs of catalytic reactions of various electronic properties and stereo properties.
  • the carbohydrate unit contains one or more ether oxygen atoms that are conducive to stabilizing catalytic species and / or improving catalytic activity, and the polarity and solubility of carbohydrates are obviously different from those of Buchwald et al. Biphenyl phosphine, QPhos of Hartwig et al., Adamantyl phosphine of Beller et al., 1,3-oxyxaphosphole phosphine ligand of Haddad et al. And phosphine ligand with arylcyclopropyl skeleton of Takasago. It also causes the phosphines of the present invention to have characteristics not possessed by other phosphines.
  • the key intermediate carbohydrate 0 compound epoxide such as methyl 2,3-anhydride-4,6-oxo-benzylidene- ⁇ -D-mannopyranoside (M. et al., Organometallics 2015, 34, 1507-1521.), methyl 2,3-anhydride-4,6-oxo-benzylidene- ⁇ -D-mannopyranoside (M.
  • dicyclohexylphosphine 2.0mL, 10.0mmol
  • 10mL of freshly distilled tetrahydrofuran 10mL
  • n-butyllithium 4.4mL, 2.4M n-hexane
  • the sodium chloride system was cooled to -10 ° C, p-toluenesulfonyl chloride (1.9g, 10.0mmol) was added under nitrogen protection, and the reaction was stirred for 6 hours.
  • the solvent was removed under reduced pressure, and the residue was dissolved with 20mL of dichloromethane, and then passed through diatoms
  • the soil was filtered and purified by silica gel column chromatography to obtain 6.0g of white solid with a yield of 96%.
  • Example 8 (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene- ⁇ -D-pyran azepronosidyl-3) -dicyclohexylphosphine sulfide
  • di-tert-butylphosphine (1.85mL, 10.0mmol) and 10mL of freshly distilled tetrahydrofuran were added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M N-hexane solution, 10.5 mmol), after about 5 minutes of dripping, return to room temperature and stir for 12 hours to prepare lithium di-tert-butylphosphonate solution.
  • diisopropylphosphine (1.48mL, 10.0mmol) was added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane solution, 10.5) was added dropwise at -78 ° C mmol), after about 5 minutes of dripping, return to room temperature, stir the reaction for 2 hours to prepare a lithium diisopropylphosphonate solution.
  • reaction was quenched by adding 0.5 mL of methanol, the solvent was removed under reduced pressure, the residue was dissolved with 20 mL of dichloromethane, then filtered through celite, and purified by silica gel column chromatography, and the mixture was purified by silica gel column layer After analysis, 2.4 g of white solid was obtained with a yield of 79%.
  • reaction solution was added with 0.5mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15mL of dichloromethane was added to dissolve the residue, and then hydrochloric acid (1M , 15mL) The solution was washed to Resistance, followed by saturated brine (20mL) The organic phase was washed three times, dried over anhydrous N ⁇ 2 SO 4, solvent extraction under reduced pressure. The product was purified by silica gel column chromatography, to give a white foamy solid 3.3g, 68% yield . mp: 181.4 ⁇ 185.4 °C.
  • reaction solution was added with 0.5mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15mL of methylene chloride was added to dissolve the residue, and then hydrochloric acid (1M, 15mL ) solution was washed to neutral, then with saturated brine (20mL) the organic phase was washed three times, dried over anhydrous N ⁇ 2 SO 4, solvent was removed under reduced pressure suction. the product was isolated by silica gel column chromatography to give an off-white foam 3.1g In a yield of 63%. mp: 158.5 ⁇ 159.9 °C. (c 1.8, CH 2 Cl 2 ).
  • reaction solution was added with 0.5mL of methanol under ice water bath, stirred for half an hour, the solvent was removed under reduced pressure, and 15mL of dichloromethane was added Dissolve the residue, and then wash the solution to neutrality with hydrochloric acid (1M, 15 mL), then wash the organic phase three times with saturated brine (20 mL), dry with anhydrous N ⁇ 2 SO 4 , remove the solvent under reduced pressure, and use silica gel Separated and purified by column chromatography to obtain 3.7g Red foamy solid, yield 81%. mp: 70.2 ⁇ 73.0 °C. (c 3.5, CH 2 Cl 2 ).
  • the cyclohexyl magnesium chloride Grignard reagent was added dropwise to the dichlorophenylphosphine solution through a double needle tip. After the addition was completed, wait for it to return to room temperature and stir for 2 hours. Take another 100mL Shrek bottle and weigh it into tetrahydrogen Lithium aluminum (370mg, 10.0mmol), inject 10mL of anhydrous tetrahydrofuran, and cool to 0 ° C with ice water, the phenylcyclohexylphosphine chloride solution The solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours.
  • the residual lithium aluminum tetrahydrogen was removed with 5 g of sodium sulfate decahydrate, and the solution was filtered through celite under nitrogen, and dried over anhydrous sodium sulfate. After that, transfer to another 100 mL Shrek bottle that has been ventilated three times. Cool to -78 ° C, and add n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.5mmol) dropwise for 5 minutes. When finished, return to room temperature and stir the reaction for 2 hours.
  • reaction solution was added with 0.5 mL of methanol under an ice water bath , Stir for half an hour, remove the solvent under reduced pressure, add 15mL of dichloromethane to the residue to dissolve, then wash the solution to neutral with hydrochloric acid (1M, 15mL), then wash the organic phase three times with saturated brine (20mL), use dried over anhydrous N ⁇ 2 SO 4, to obtain about 4.6 g of crude product.
  • reaction solution was added with 0.5 mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and the solution was washed with saturated ammonium chloride, and the organic phase was separated, Anhydrous N ⁇ 2 SO 4 was dried, and the solvent was removed under reduced pressure.
  • the mixture was recrystallized from methanol to obtain 3.3 g of (Rp)-and (Sp)-(methyl 3-deoxy-4,6-oxo-benzene) as white solids.
  • Methylene- ⁇ -D-azopyranoside-3)-(2-tolyl) phosphine mixture yield 85%.
  • the solution was filtered through diatomaceous earth under nitrogen. After adding anhydrous sodium sulfate to dry, the solution was transferred to another pumped and ventilated three times. 50mL Shrek bottle. Cooled to -78 °C, to which n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.6mmol) was added dropwise, after 5 minutes of dripping, returned to room temperature, and stirred to react for 1 hour.
  • dicyclohexylphosphine 2.0mL, 10.0mmol
  • n-butyllithium 4.4mL, 2.4M n-hexane solution, 10.5mmol
  • dicyclohexylphosphine (2.0mL, 10.0mmol) was added to a 50mL Shrek bottle, and 10mL of freshly distilled tetrahydrofuran was added.
  • N-butyllithium (4.4mL, 2.4M n-hexane was added dropwise at -78 ° C) Solution, 10.5 mmol), after about 5 minutes, the solution was returned to room temperature, and the reaction solution was stirred for 2 hours to prepare a lithium dicyclohexylphosphine solution.
  • dicyclohexylphosphine (2.0mL, 10.0mmol) was added to a 50mL Shrek bottle, and 10mL of freshly distilled tetrahydrofuran was added.
  • N-butyllithium (4.4mL, 2.4M n-hexane was added dropwise at -78 ° C) Solution, 10.5 mmol), after about 5 minutes, the solution was returned to room temperature, and the reaction solution was stirred for 2 hours to prepare a lithium dicyclohexylphosphine solution.
  • phosphorus trichloride (0.68g, 5.0mmol) was added, Slowly return to -40 ° C and stir for 1 hour to prepare a bis (2-biphenyl) phosphine chloride solution. Cut in lithium metal (200mg) and stir for 24 hours. Take another 50mL Shrek bottle and weigh it into the A 2,3-anhydride-4,6-oxo-benzylidene- ⁇ -D-pyrano-aluloside (2.9g, 9.0mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve Add lithium bis (2-biphenyl) phosphonate solution to the double needle tip, and stir the reaction for 6 hours.
  • reaction solution was added with 0.5 mL of methanol under an ice water bath, stirred for half an hour, and the solvent was removed under reduced pressure. Dissolve the residue in 15 mL of dichloromethane, and then wash the solution to neutrality with hydrochloric acid (1 M, 15 mL), then wash the organic phase three times with saturated brine (20 mL), dry with anhydrous N 2 SO 4 , and remove the solvent under reduced pressure.
  • the product is separated and extracted by silica gel column chromatography To give a white foamy solid 3.6g, 77% yield. mp: 70.4 ⁇ 73.8 °C.
  • dicyclohexylphosphine 2.0mL, 10.0mmol
  • 10mL freshly distilled tetrahydrofuran 10mL
  • n-butyllithium 4.4mL, 2.4M n-hexane
  • dicyclohexylphosphine 2.0mL, 10.0mmol
  • 10mL freshly distilled tetrahydrofuran 10mL
  • n-butyllithium 4.4mL, 2.4M n-hexane
  • Example 53 4-Methoxy-9- (methyl 3-deoxy-4,6-oxo-benzylidene- ⁇ -D-pyran azeposide-3) -9-phosphafluorene
  • Example 54 9- (Methyl 3-deoxy-4,6-oxo-benzylidene- ⁇ -D-pyran azeposide-3) -9-phosphafluorene
  • the residual lithium aluminum hydride was removed with 5 g of sodium sulfate decahydrate, and the solution was passed through diatom under nitrogen After filtration, add anhydrous sodium sulfate to dry, transfer to another 50mL Shrek bottle that has been pumped and ventilated three times. Cool to -78 ° C, and add n-butyl lithium (4.38mL, 2.4M n-hex) to it dropwise Alkane solution, 10.6 mmol), after about 5 minutes of dripping, return to room temperature and stir the reaction for 1 hour.
  • Example 58 [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene- ⁇ -D-azopyranoside-3) -dicyclohexylphosphine]- (N, N-dimethylbenzylamine-2- ⁇ 2 -C, N) -palladium (II) chloride
  • Example 60 [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene- ⁇ -D-azopyranoside-3) -dicyclohexylphosphine]- (2'-Methylaminobiphenyl-2- ⁇ 2 -C, N) -palladium (II) methanesulfonate
  • Example 64 [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene- ⁇ -D-azopyranoside-3) -dicyclohexylphosphine]- (2'-aminophenylethane-2- ⁇ 2 -C, N) -palladium (II) chloride
  • the catalyst is [(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene- ⁇ -D-pyran azreosidino-3) -dicyclohexylphosphine]-(N , N-dimethylbenzylamino-2- ⁇ 2 -C, N) -palladium (II) chloride.
  • the catalyst is ⁇ (N, N-dimethylbenzylamino-2- ⁇ 2 -C, N)-[(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene Group- ⁇ -D-azopyranoside-3) -dicyclohexylphosphine] palladium (II) chloride ⁇ .

Abstract

Provided by the present invention are carbohydrate monophosphines represented by general formula Ia, Ib, IIa or IIb, comprising mixtures represented by Ia and Ib having different phosphorus atom configurations, or mixtures represented by IIa and IIb having different phosphorus atom configurations, and a method for preparing same; the present invention describes borane adducts, oxides, sulfides or selenides of the carbohydrate monophosphines; in addition, further provided by the present invention is a palladium complex complexed with a carbohydrate monophosphine; a catalytic system composed of a carbohydrate monophosphine and palladium salt or a complex thereof, or a use of a palladium complex complexed with a carbohydrate monophosphine in catalyzing organic reactions is also a part of the present invention, in particular a use in catalyzing coupling reactions of (pseudo) haloaromatics to form new C-C or C-N bonds.

Description

碳水化合物单膦、它们的制备方法和用途Carbohydrate monophosphine, their preparation method and use 技术领域Technical field
本发明涉及新颖的带吡喃阿卓糖或吡喃艾杜糖单元的手性单膦配体，包括带P-手性的单膦配体，它们的制备方法，它们配位的过渡金属络合物，以及它们与过渡金属组成的催化体系在催化有机反应中的用途，特别是催化C-C、C-N和C-O键形成反应中的用途。The present invention relates to novel chiral monophosphine ligands with azulose or idylpyranose units, including P-chiral monophosphine ligands, their preparation methods, and their coordinated transition metal complexes Compounds, and the use of catalytic systems composed of them and transition metals in catalyzing organic reactions, especially in the formation of CC, CN, and CO bonds.
背景技术Background technique
多种有机反应可由过渡金属络合物高效催化实现，因此在药物和有机材料的制备中过渡金属络合物催化剂常常起到重要作用。过渡金属络合物催化剂的性能本质上取决于金属元素本身，但能高效地实现丰富多样的有机转化，包括不对称催化转化，还有来自于其周边的配体对金属中心性质调控的贡献。其中，有机配体尤其是有机膦配体，对金属中心电子性质和金属中心周围立体环境的调控起到了重要作用。配位原子的给电子及接受反馈电子的能力调控了金属中心的电子性质并会影响其它配体与金属中心的配位作用，配位原子的半径及其占据的周边尺寸会影响到金属中心的配位数和其它配体(包括底物)的配位排布。因此，配体的电子性质与立体性质综合地影响了催化反应的各个步骤，对优化金属络合物高效地催化有机转化起到了关键作用。A variety of organic reactions can be efficiently catalyzed by transition metal complexes, so transition metal complex catalysts often play an important role in the preparation of drugs and organic materials. The performance of the transition metal complex catalyst essentially depends on the metal element itself, but it can efficiently realize a variety of organic conversions, including asymmetric catalytic conversion, and the contribution of the surrounding ligands to the regulation of the nature of the metal center. Among them, organic ligands, especially organic phosphine ligands, play an important role in the electronic properties of the metal center and the regulation of the three-dimensional environment around the metal center. The ability of the coordination atom to donate electrons and accept feedback electrons regulates the electronic properties of the metal center and affects the coordination of other ligands to the metal center. The radius of the coordination atom and the peripheral size it occupies will affect the metal center. The coordination number and the coordination arrangement of other ligands (including substrates). Therefore, the electronic and stereoscopic properties of the ligand comprehensively affect the various steps of the catalytic reaction, and play a key role in optimizing the metal complex to efficiently catalyze the organic conversion.
在过渡金属催化的许多有机反应中，偶联反应是非常重要的一类反应。因此，研发高效的非手性或手性膦配体以实现高效的催化偶联反应受到人们重视。Buchwald等人研发了二联苯类膦配体(S.L.Buchwald，et al，US 6，307，087；WO 2009/076622)及其配位的钯络合物(S.L.Buchwald WO 2011/008725)。Hartwig等人研发出二茂铁骨架的多取代苯基二特丁基膦QPhos(J.F.Hartwig，et al.，WO 2002/011883)。Beller等人制备了带大立体位阻金刚基的膦配体(M.Beller，et al.，CN 101195641)，而B.P.Carrow等人研制了带三个金刚基的膦配体(WO 2017/075581)。基于二联苯的骨架，Haddad等人研发出1,3-oxaphosphole官能团的手性膦配体(WO 2011/126917)，而Shekhar等人研发出带磷杂环烷基的膦配体(S.Shekhar et al.，US 2013/0217876)。Takasago公司研发出带芳基环丙基骨架的膦配体(K.Suzuki，et al.，WO 2013/032035)。相关代表性的膦配体的结构显示如 下:Among many organic reactions catalyzed by transition metals, the coupling reaction is a very important type of reaction. Therefore, the development of highly efficient achiral or chiral phosphine ligands to achieve efficient catalytic coupling reactions has attracted attention. Buchwald et al. Developed biphenyl phosphine ligands (S.L. Buchwald, et al, US 6,307, 087; WO 2009/076622) and their coordinated palladium complexes (S. L. Buchwald WO 2011/008725). Hartwig et al. Developed a multi-substituted phenyl di-tert-butylphosphine QPhos with a ferrocene skeleton (J. F. Hartwig, et al., WO 2002/011883). Beller et al. Prepared phosphine ligands with large sterically hindered adamantyl groups (M. Beller, et al., CN 101195641), while BPCarrow et al. Developed phosphine ligands with three adamantyl groups (WO2017 / 075581 ). Based on the biphenyl skeleton, Haddad et al. Developed a chiral phosphine ligand with a 1,3-oxaphosphole functional group (WO 2011/126917), and Shekhar et al. Developed a phosphine ligand with a phosphorus heterocycloalkyl group (S. Shekhar et al., US 2013/0217876). Takasago developed a phosphine ligand with an arylcyclopropyl skeleton (K. Suzuki, et al., WO 2013/032035). The structure of related representative phosphine ligands is shown below:
Figure PCTCN2019088461-appb-000001
Figure PCTCN2019088461-appb-000001
需要过渡金属络合物催化的有机反应的种类很多，对膦配体的电子性质和立体性质要求也各有不同。往往在同一个催化反应中不同的膦配体对不同的底物在催化性能上的表现往往也各有千秋。为了便于与产物分离的需求也需要有性质不同，包括极性和溶解度不同的膦配体。催化反应的种类众多且底物的数目种类也多，因此为了优化各类催化反应需要多种多样的类型和性质的膦配体，所以研制新型高效的膦配体一直是催化研究领域的重要基础工作。前期研究发现(J.-C.Shi，et al.，Tetrahedron Letters 2014，55，2904-2907)碳水化合物单膦，(甲基4,6-氧-苯甲叉基-3-脱氧-ɑ-D-吡喃阿卓糖苷基-3)-二苯基膦，在钯催化溴带芳烃的Suzuki偶联反应中有较好的催化性能，但在催化氯代芳烃这类底物中的性能较差，可能的原因是这个配体的磷原子上带有2个给电子能力较弱的苯基的缘故。鉴于带碳水化合物单元的膦配体从骨架的结构上明显有别于上述代表性膦配体如二联苯、二茂铁、金刚基及环丙基的骨架结构，如果把连接在吡喃阿卓糖骨架上的磷原子的取代基更替为其它取代基和或在其它种类的碳水化合物骨架上接上磷原子，这样就能研制出结构和性能新颖的膦配体，来丰富和满足过渡金属催化体系对特定膦配体的需求。There are many types of organic reactions that need to be catalyzed by transition metal complexes, and the electronic and stereoscopic properties of phosphine ligands also have different requirements. In the same catalytic reaction, different phosphine ligands often perform differently on different substrates in terms of catalytic performance. In order to facilitate separation from the product, phosphine ligands with different properties including different polarities and solubility are also required. There are many types of catalytic reactions and many kinds of substrates. Therefore, in order to optimize various types of catalytic reactions, various types and properties of phosphine ligands are needed, so the development of new and efficient phosphine ligands has always been an important foundation in the field of catalytic research jobs. Early research found (J.-C. Shi, et.al., Tetrahedron Letters 2014, 55, 2904-2907) carbohydrate monophosphine, (methyl 4,6-oxo-benzylidene-3-deoxy-ɑ- D-Aranopyranoside-3) -diphenylphosphine has better catalytic performance in palladium-catalyzed Suzuki coupling reaction of brominated aromatic hydrocarbons, but it has better performance in catalyzing substrates such as chlorinated aromatic hydrocarbons Poor, the possible reason is that the phosphorus atom of this ligand has two phenyl groups with weak electron donating ability. In view of the fact that the phosphine ligands with carbohydrate units are obviously different from the skeleton structure of the above-mentioned representative phosphine ligands such as biphenyl, ferrocene, adamantyl and cyclopropyl, if they are connected to pyran The substitution of the phosphorus atom on the dextrose skeleton is replaced by other substituents or the phosphorus atom is attached to other kinds of carbohydrate skeletons, so that phosphine ligands with novel structure and performance can be developed to enrich and satisfy the transition metal Catalytic system requirements for specific phosphine ligands.
发明概述Summary of the invention
本发明涉及:(1)碳水化合物单膦；(2)碳水化合物单膦的硼烷加合物、氧化物、硫化物和硒化物；(3)碳水化合物单膦的制备方法；(4)碳水化合物单膦配位的钯络合物；(5)碳水化合物单膦和过渡金属组成的催化体系；(6)钯络合物与碳水化合物单膦组成的催化体系、或碳水化合物单膦配位的钯络合物在催化(拟)卤代芳烃为底物的偶联反应中的用途。The invention relates to: (1) carbohydrate monophosphine; (2) borane adduct, oxide, sulfide and selenide of carbohydrate monophosphine; (3) preparation method of carbohydrate monophosphine; (4) carbohydrate Palladium complex with compound monophosphine coordination; (5) Catalytic system composed of carbohydrate monophosphine and transition metal; (6) Catalytic system composed of palladium complex with carbohydrate monophosphine, or coordination of carbohydrate monophosphine Of palladium complex in catalyzing the coupling reaction of (pseudo) halogenated aromatic hydrocarbon as substrate.
发明公开Invention Disclosure
第一方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物：In a first aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations:
Figure PCTCN2019088461-appb-000002
Figure PCTCN2019088461-appb-000002
其中，among them,
碳水化合物单元可以是ɑ-D-吡喃阿卓糖、β-D-吡喃阿卓糖、ɑ-D-吡喃艾杜糖或β-D-吡喃艾杜糖单元；The carbohydrate unit may be an ɑ-D-aradanose, β-D-aradanose, ɑ-D-iduran or β-D-idulan unit;
R 1选自H、(C1-C6)烷基、(C6-C10)芳基或-CH 2(C6-C10)芳亚甲基，这里的(C6-C10)芳基和-CH 2(C6-C10)芳亚甲基可以有1到3个独立地选自硝基、(C1-C6)烷基或-O(C1-C6)烷氧基的取代基； R 1 is selected from H, (C1-C6) alkyl, (C6-C10) aryl or -CH 2 (C6-C10) aryl methylene, here (C6-C10) aryl and -CH 2 (C6 -C10) arylmethylene may have 1 to 3 substituents independently selected from nitro, (C1-C6) alkyl or -O (C1-C6) alkoxy;
Figure PCTCN2019088461-appb-000003
Figure PCTCN2019088461-appb-000003
R 2和R 3各自独立地选自H、(C1-C6)烷基、(C1-C8)酰基或-CH 2(C6-C10)芳亚甲基，或者R 2和R 3组合为甲叉基＝CR 7R 8，这里的R 7和R 8可各自独立地选自H、(C1-C6)烷基、(5到6元的)环烷基或(C6-C10)芳基； R 2 and R 3 are each independently selected from H, (C1-C6) alkyl, (C1-C8) acyl or -CH 2 (C6-C10) aryl methylene, or R 2 and R 3 are combined to form methylene Radical = CR 7 R 8 , where R 7 and R 8 may each be independently selected from H, (C1-C6) alkyl, (5- to 6-membered) cycloalkyl or (C6-C10) aryl;
Figure PCTCN2019088461-appb-000004
Figure PCTCN2019088461-appb-000004
R 4和R 5各自独立地选自H、OH、SH、(C1-C8)烷基、(C3-C10)环烷基、(5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基、二茂铁基或R 4和R 5组合为9-磷杂芴基，但R 4和R 5之一选自H、OH或SH时另一个R 4或R 5则不能为H、OH或SH，这里的(C3-C10)环烷基、(5-6元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳 基、二茂铁基、-CH 2(C6-C10)芳亚甲基和9-磷杂芴基中可以有1到3个独立地选自(C1-C6)烷基(可以带F原子)、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷基氨基的取代基，而(5-6元)杂环烷基和(C4-C20)杂芳基中的杂原子选自O、N或S； R 4 and R 5 are each independently selected from H, OH, SH, (C1-C8) alkyl, (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aromatic Group, (C4-C20) heteroaryl, ferrocenyl or R 4 and R 5 are combined as 9-phosphafluorenyl, but one of R 4 and R 5 is selected from H, OH or SH, the other R 4 Or R 5 can not be H, OH or SH, here (C3-C10) cycloalkyl, (5-6 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl , Ferrocenyl, -CH 2 (C6-C10) arylmethylene and 9-phosphafluorenyl can have 1 to 3 independently selected from (C1-C6) alkyl (may have F atoms), -O (C1-C6) alkoxy or -N (C1-C6) 2 dialkylamino substituent, and (5-6 member) heterocycloalkyl and (C4-C20) heteroaryl The atom is selected from O, N or S;
R 6选自H、(C1-C6)烷基、(C1-C8)酰基、-CH 2(C6-C10)芳亚甲基或R 9SO 2磺酰基，这里的R 9选自(C1-C6)烷基或(C6-C10)芳基； R 6 is selected from H, (C1-C6) alkyl, (C1-C8) acyl, -CH 2 (C6-C10) arylmethylene or R 9 SO 2 sulfonyl, where R 9 is selected from (C1- C6) alkyl or (C6-C10) aryl;
当碳水化合物单元为(甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-2-)时：且R 4和R 5均为苯基时，R 6则不为H； When the carbohydrate unit is (methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosid-2-): and when R 4 and R 5 are both phenyl , R 6 is not H;
当碳水化合物单元为甲基(3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3-)时：1)且R 4和R 5均为苯基时，R 6则不为H或甲基；2)且R 4为苯基而同时R 5为甲基时，R 6则不为H或甲基；3)且R 4为苯基同时R 5为H时，R 6则不为H。 When the carbohydrate unit is methyl (3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3-): 1) and R 4 and R 5 are both benzene when the group, R 6 is not H or methyl; 2) and R 4 is phenyl while R 5 is a methyl group, R 6 is not H or methyl; 3) and R 4 is phenyl while R When 5 is H, R 6 is not H.
第二方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 1是(C1-C6)烷基是可选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、或正己基，碳水化合物单元、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义同第一方面。 In a second aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 1 is (C1-C6) alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl, carbohydrate unit, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第三方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 1是(C6-C10)芳基时可选自苯基、对甲苯基、对硝基苯基、对甲氧基苯基或萘基，碳水化合物单元、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义同第一方面。 In a third aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 1 is (C6-C10) aryl, it may be selected from phenyl, p-tolyl, p-nitrophenyl, p-methoxyphenyl or naphthyl, carbohydrate unit, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第四方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 1是CH 2(C6-C10)芳基亚甲基时可选自苯基亚甲基、对甲苯基亚甲基、对甲氧基苯基亚甲基或萘基亚甲基，碳水化合物单元、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义同第一方面。 In a fourth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 1 is CH 2 (C6-C10) aryl methylene, it can be selected from phenyl methylene, p-tolyl methylene, p-methoxy phenyl methylene or naphthyl methylene, carbohydrate Units, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第五方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 2或R 3是(C1-C6)烷基时可选自甲基、乙基、正丙基、正丁基、正戊基或正己基，碳水化合物单元、R 1、R 4、R 5、R 6和R 9的定义同第一方面。 In a fifth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 2 or R 3 is (C1-C6) alkyl, it may be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl, carbohydrate unit, R 1 , R 4 , R 5 , R 6 and R 9 are as defined in the first aspect.
第六方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包 括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 2或R 3是-CH 2(C6-C10)芳基亚甲基时可选自苯亚甲基、对甲基苯亚甲基、对甲氧基苯亚甲基或萘亚甲基，碳水化合物单元、R 1、R 4、R 5、R 6和R 9的定义同第一方面。 In a sixth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 2 or R 3 is -CH 2 (C6-C10) aryl methylene, it may be selected from benzylidene, p-toluene methylene, p-methoxybenzylidene or naphthalene methylene, Carbohydrate units, R 1 , R 4 , R 5 , R 6 and R 9 are as defined in the first aspect.
第七方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 2或R 3是(C1-C8)酰基时可选自甲酰基、乙酰基、丙酰基、苯甲酰基或苯乙酰基，碳水化合物单元、R 1、R 4、R 5、R 6和R 9的定义同第一方面。 In a seventh aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 2 or R 3 is (C1-C8) acyl, it may be selected from formyl, acetyl, propionyl, benzoyl or phenylacetyl, carbohydrate unit, R 1 , R 4 , R 5 , R 6 and R The definition of 9 is the same as the first aspect.
第八方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 2和R 3可以组合为甲叉基＝CR 7R 8，这里R 7和R 8可各自独立地选自H、甲基、乙基、正丙基、正丁基、苯基、对甲苯基、对甲氧基苯基或萘基，碳水化合物单元、R 1、R 4、R 5、R 6和R 9的定义同第一方面。 In an eighth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 2 and R 3 can be combined as methylene = CR 7 R 8 , where R 7 and R 8 can each be independently selected from H, methyl, ethyl, n-propyl, n-butyl, phenyl, p-toluene Group, p-methoxyphenyl or naphthyl, carbohydrate units, R 1 , R 4 , R 5 , R 6 and R 9 are as defined in the first aspect.
第九方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4和R 5不能同时为H、OH、和SH，既R 4和R 5中的一个选自H、OH或SH时，则另一个R 4和R 5不能选自H、OH或SH，而只能选自第一方面有关R 4和R 5定义的其余部分，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a ninth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 4 and R 5 can not both be H, OH, and SH, both R a is selected from H 4 and R 5 are, when the OH or SH, the other of R 4 and R 5 can not be selected from H, OH or SH, It can only be selected from the rest of the definition of R 4 and R 5 in the first aspect. The definitions of carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are the same as those in the first aspect.
Figure PCTCN2019088461-appb-000005
Figure PCTCN2019088461-appb-000005
其中R 4或R 5之一为OH或SH时，大多数的三价R 2POH或R 2PSH(Ia-O(S)H、Ib-O(S)H、IIa-O(S)H或IIb-O(S)H)(带有-O(S)H的后缀的通式表明其R 4或R 5之一为OH或SH)会异构为相应的五价的、含P＝O或P＝S官能团的相应的异构体(IIIa、IIIb、IVa或IVb)，因此这类化合物更经常被称为二级膦氧化物或二级膦硫化物，但在后过渡金属存在时，随着三价R 2POH或R 2PSH膦中的磷原子不断地与过渡金属配位又使得二级膦氧(硫)化物不断地转化为三价R 2POH或R 2PSH膦配体。由于三价R 2POH或R 2PSH多数以五价含P＝O或P＝S的异构体形式存在，所以这类带OH或SH的碳水化合物膦配体较三级膦具有更好的耐氧化性，这是这类磷原子上带羟基或巯基的膦配体具有的特点之一。 When one of R 4 or R 5 is OH or SH, most trivalent R 2 POH or R 2 PSH (Ia-O (S) H, Ib-O (S) H, IIa-O (S) H Or IIb-O (S) H) (the general formula with the suffix of -O (S) H indicates that one of R 4 or R 5 is OH or SH) will be isomerized to the corresponding pentavalent, containing P = O or P = the corresponding isomer of the S functional group (IIIa, IIIb, IVa or IVb), so such compounds are more often called secondary phosphine oxides or secondary phosphine sulfides, but in the presence of late transition metals , As the phosphorus atom in the trivalent R 2 POH or R 2 PSH phosphine continuously coordinates with the transition metal and the secondary phosphine oxy (sulfur) compound is continuously converted into the trivalent R 2 POH or R 2 PSH phosphine ligand . Since trivalent R 2 POH or R 2 PSH mostly exists in the form of pentavalent isomers containing P = O or P = S, such carbohydrate phosphine ligands with OH or SH have better performance than tertiary phosphines Oxidation resistance, which is one of the characteristics of this kind of phosphine ligands with hydroxyl groups or mercapto groups on the phosphorus atom.
第十方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4或R 5是(C1-C8)烷基时可独立地选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、特戊基或特辛基，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a tenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein When R 4 or R 5 is (C1-C8) alkyl, it can be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tert-amyl or tert-butyl Octyl, carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十一方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合 物，其中R 4或R 5是(C3-C10)环烷基时可各自独立地选自环丙基、环丁基、环戊基、环己基或金刚基，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In an eleventh aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 4 or R 5 is (C3-C10) cycloalkyl, each may be independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, carbohydrate unit, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十二方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4或R 5是(C6-C20)芳基时可选自苯基、4-甲苯基、2-甲苯基、2-(二甲氨基)苯基、4-(二甲氨基)苯基、2-甲氧基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、3,5-双三氟甲基苯基、2,6-二甲基苯基、2,6-二甲氧基苯基、2,6-双(二甲氨基)苯基、3,4,5-三甲氧基苯基、2-联苯基、2’-甲基-2-联苯基、2’-异丙基-2-联苯基、2’-甲氧基-2-联苯基、2’-异丙氧基-2-联苯基、2’-二甲氨基-2-联苯基、2’,6’-二甲基-2-联苯基、2’,6’-二异丙基-2-联苯基、2’,4’,6’-三异丙基-2-联苯基、2’,6’-二甲氧基-2-联苯基、2’,6’-二异丙氧基-2-联苯基、2’,6’-双(二甲氨基)-2-联苯基、2,6-二苯基苯基、2,6-双(2’,6’-二甲氧基苯基)苯基、2,6-双(2’,6’-二异丙氧基苯基)苯基、2,6-双(2’,6’-二甲基苯基)苯基、2,6-双(2’,4’,6’-三甲基苯基)苯基、2,6-双(2’,6’-二异丙基苯基)苯基、2,6-双(2’,4’,6’-三异丙基苯基)苯基、萘基、1,1’-2-联萘基、或1,1’-2’-甲氧基-2-联萘基，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a twelfth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 4 or R 5 is (C6-C20) aryl, it can be selected from phenyl, 4-tolyl, 2-tolyl, 2- (dimethylamino) phenyl, 4- (dimethylamino) phenyl , 2-methoxyphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-bistrifluoromethylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-bis (dimethylamino) phenyl, 3,4,5-trimethoxyphenyl, 2-biphenyl Group, 2'-methyl-2-biphenyl, 2'-isopropyl-2-biphenyl, 2'-methoxy-2-biphenyl, 2'-isopropoxy-2- Biphenyl, 2'-dimethylamino-2-biphenyl, 2 ', 6'-dimethyl-2-biphenyl, 2', 6'-diisopropyl-2-biphenyl, 2 ', 4', 6'-triisopropyl-2-biphenyl, 2 ', 6'-dimethoxy-2-biphenyl, 2', 6'-diisopropoxy-2 -Biphenyl, 2 ', 6'-bis (dimethylamino) -2-biphenyl, 2,6-diphenylphenyl, 2,6-bis (2', 6'-dimethoxy) Phenyl) phenyl, 2,6-bis (2 ', 6'-diisopropoxy Group) phenyl, 2,6-bis (2 ', 6'-dimethylphenyl) phenyl, 2,6-bis (2', 4 ', 6'-trimethylphenyl) phenyl, 2,6-bis (2 ', 6'-diisopropylphenyl) phenyl, 2,6-bis (2', 4 ', 6'-triisopropylphenyl) phenyl, naphthyl, 1,1'-2-binaphthyl, or 1,1'-2'-methoxy-2-binaphthyl, carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R The definitions of 8 and R 9 are the same as the first aspect.
第十三方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4或R 5是(C4-C20)杂芳基时可选自2-呋喃基、2-噻吩基、5-甲基2-呋喃基、5-甲基-2-噻吩基、2-吡啶基、3-吡啶基或8-喹啉基，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a thirteenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 4 or R 5 is (C4-C20) heteroaryl, it can be selected from 2-furyl, 2-thienyl, 5-methyl 2-furyl, 5-methyl-2-thienyl, 2- Pyridyl, 3-pyridyl or 8-quinolinyl, carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十四方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4或R 5是二茂铁基时可选自二茂铁基、乙酰基二茂铁基或(1-二甲基氨基-乙基)二茂铁基-2-，碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a fourteenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 4 or R 5 is ferrocenyl, it can be selected from ferrocenyl, acetylferrocenyl or (1-dimethylamino-ethyl) ferrocenyl-2-, carbohydrate unit, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十五方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合 物，其中R 6是(C1-C6)烷基时可选自甲基、乙基、正丙基、正丁基、正戊基或正己基，碳水化合物单元、R 1、R 2、R 3、R 4、R 5、R 7、R 8和R 9的定义同第一方面。 In a fifteenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 6 is (C1-C6) alkyl, it can be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4. The definitions of R 5 , R 7 , R 8 and R 9 are the same as the first aspect.
第十六方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 6是-CH 2(C6-C10)芳亚甲基时可选苯亚甲基、4-甲氧基苯亚甲基或萘亚甲基，碳水化合物单元、R 1、R 2、R 3、R 4、R 5、R 7、R 8和R 9的定义同第一方面。 In a sixteenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 6 is -CH 2 (C6-C10) aryl methylene, benzyl methylene, 4-methoxybenzylidene or naphthalene methylene, carbohydrate unit, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十七方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 6是(C1-C8)酰基时可选自甲酰基、乙酰基、丙酰基、苯甲酰基或苯乙酰基，碳水化合物单元、R 1、R 2、R 3、R 4、R 5、R 7、R 8和R 9的定义同第一方面。 In a seventeenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 6 is (C1-C8) acyl, it may be selected from formyl, acetyl, propionyl, benzoyl or phenylacetyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4 , R 5 , The definitions of R 7 , R 8 and R 9 are the same as the first aspect.
第十八方面，本发明提供了碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 6是R 9SO 2磺酰基时可精选自甲磺酰基、苯甲磺酰基或对甲苯磺酰基，碳水化合物单元、R 1、R 2、R 3、R 4、R 5、R 7、R 8和R 9的定义同第一方面。 In an eighteenth aspect, the present invention provides a carbohydrate monophosphine having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, Where R 6 is R 9 SO 2 sulfonyl, it can be selected from methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, carbohydrate unit, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are as defined in the first aspect.
第十九方面，本发明提供了碳水化合物单膦的硼烷加合物，它们的通式为Va、Vb、VIa或VIb，还可以是Va和Vb的混合物或VIa和VIb的混合物，除了R 4或R 5不为OH或SH外，R 4和R 5定义的其它部分以及碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义与限定同第一方面。 In a nineteenth aspect, the present invention provides borane adducts of carbohydrate monophosphines, which have the general formula Va, Vb, VIa or VIb, and may also be a mixture of Va and Vb or a mixture of VIa and VIb except R 4 or R 5 is not OH or SH, other parts defined by R 4 and R 5 and carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are defined and defined in the same way first.
Figure PCTCN2019088461-appb-000006
Figure PCTCN2019088461-appb-000006
第二十方面，本发明提供了碳水化合物单膦的氧化物、硫化物或硒化物，它们具有的通式为VIIa、VIIb、VIIIa或VIIIb，还可以是VIIa和VIIb的混合物或VIIIa和VIIIb的混合物，除了R 4或R 5不为H、OH或SH外，R 4和R 5定义的其余部分及碳水化合物单元、R 1、R 2、R 3、R 6、R 7、R 8和R 9的定义同第一方面。 In a twentieth aspect, the present invention provides oxides, sulfides, or selenides of carbohydrate monophosphines, which have the general formula VIIa, VIIb, VIIIa, or VIIIb, and may also be a mixture of VIIa and VIIb or VIIIa and VIIIb Mixture, except that R 4 or R 5 are not H, OH or SH, the rest of R 4 and R 5 are defined as well as carbohydrate units, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R The definition of 9 is the same as the first aspect.
Figure PCTCN2019088461-appb-000007
Figure PCTCN2019088461-appb-000007
第二十一方面，本发明提供了上面描述的碳水化合物单膦(通式为Ia、Ib或它们的混合物，或IIa、IIb或它们的混合物)及其硼烷加合物(通式为Va、Vb或它们的混合物，或VIa、VIb或它们的混合物)的制备方法。概括地讲，这些碳水化合物单膦及其硼烷加合物可以通过Scheme 1描述的路径制备，其中通式IX包含了2,3-酐-ɑ-D-吡喃甘露糖苷、2,3-酐-β-D-吡喃甘露糖苷、2,3-酐-ɑ-D-吡喃塔罗糖苷、和2,3-酐-β-D-吡喃塔罗糖苷这四类已知制备方法的碳水化合物环氧化物，这里的R 1、R 2、R 3的定义同第一方面，而通式X可以包含了2,3-酐-ɑ-D-吡喃阿洛糖苷、2,3-酐-β-D-吡喃阿洛糖苷、2,3-酐-ɑ-D-吡喃古罗糖苷、和2,3-酐-β-D-吡喃古罗糖苷这四类已知制备方法的碳水化合物环氧化物，这里的R 1、R 2、R 3的定义同第一方面。具有通式IX或通式X的环氧化物分别与1到4当量的MPR 4R 5[M＝Li，Na，K，MgX 1(X 1＝Cl，Br，I)]，其制备方法可以是用HPR 4R 5用相应的碱夺氢，或者Cl-PR 4R 5或Ph-PR 4R 5用相应的金属断裂Cl-P或Ph-P键，在-80℃到120℃温度范围内反应，优选反应温度为-40℃到80℃，即可得到碳水化合物单膦(通式为Ia、Ib或它们的混合物，或IIa、IIb或它们的混合物)，而此时R 6为H而R 4和R 5不为OH或SH。也可以在1到4当量的碱，如叔丁醇钠或叔丁醇钾，存在下，具有通式IX或通式X的环氧化物分别与HPR 4R 5在-20℃到150℃温度范围内反应，优选反应温度为0℃到100℃，制备得到碳水化合物单膦，此时R 6为H而R 4和R 5不为OH或SH。可进一步利用已知的仲醇醚化或酯化方法获得R 6为(C1-C6)烷基、-CH 2(C6-C10)芳亚甲基、(C1-C8)酰基或R 9SO 2磺酰基，这里的R 9选自(C1-C6)烷基或(C6-C10)的芳基，的碳水化合物单膦。 In the twenty-first aspect, the present invention provides the above-described carbohydrate monophosphines (general formula Ia, Ib or mixtures thereof, or IIa, IIb or mixtures thereof) and borane adducts (general formula Va , Vb or mixtures thereof, or VIa, VIb or mixtures thereof). Broadly speaking, these carbohydrate monophosphines and their borane adducts can be prepared by the route described in Scheme 1, where the general formula IX contains 2,3-anhydride-ɑ-D-mannopyranoside, 2,3- Anhydride-β-D-pyranoside, 2,3-anhydride-ɑ-D-pyrantaloside, and 2,3-anhydride-β-D-pyrantaloside Carbohydrate epoxides, where R 1 , R 2 , and R 3 are as defined in the first aspect, and the general formula X may include 2,3-anhydride-ɑ-D-allopyranoside, 2,3 -Anhydride-β-D-pyranoglucoside, 2,3-anhydride-ɑ-D-glucopyranoside, and 2,3-anhydride-β-D-glucopyranoside For the carbohydrate epoxide of the preparation method, the definitions of R 1 , R 2 and R 3 here are the same as the first aspect. An epoxide having the general formula IX or X and 1 to 4 equivalents of MPR 4 R 5 [M = Li, Na, K, MgX 1 (X 1 = Cl, Br, I)], the preparation method of which can be Use HPR 4 R 5 to extract hydrogen with the corresponding base, or Cl-PR 4 R 5 or Ph-PR 4 R 5 to break the Cl-P or Ph-P bond with the corresponding metal, in the temperature range of -80 ℃ to 120 ℃ Internal reaction, preferably the reaction temperature is -40 ℃ to 80 ℃, you can get carbohydrate monophosphine (the general formula is Ia, Ib or their mixture, or IIa, IIb or their mixture), and R 6 is H R 4 and R 5 are not OH or SH. Also in the presence of 1 to 4 equivalents of base, such as sodium tert-butoxide or potassium tert-butoxide, an epoxide having the general formula IX or general formula X and HPR 4 R 5 at a temperature of -20 ° C to 150 ° C, respectively For the reaction in the range, the reaction temperature is preferably 0 ° C to 100 ° C, and a carbohydrate monophosphine is prepared, in which case R 6 is H and R 4 and R 5 are not OH or SH. R 6 is (C1-C6) alkyl, -CH 2 (C6-C10) aryl methylene, (C1-C8) acyl or R 9 SO 2 can be further obtained by known secondary alcohol etherification or esterification Sulfonyl, where R 9 is selected from (C1-C6) alkyl or (C6-C10) aryl, a carbohydrate monophosphine.
上个自然段描述的碳水化合物单膦，与1到5当量的硼烷BH 3的四氢呋喃或二甲硫醚的加合物在-40℃到60℃温度范围内反应，优选计量为1.1到2.0当量和优选的反应温度为-10℃到40℃，可以得到碳水化合物单膦硼烷加合物，此 时R 4和R 5不为OH或SH。 The carbohydrate monophosphine described in the last paragraph is reacted with an adduct of 1 to 5 equivalents of borane BH 3 in tetrahydrofuran or dimethyl sulfide in a temperature range of -40 ° C to 60 ° C, preferably 1.1 to 2.0 The equivalent weight and the preferred reaction temperature are -10 ° C to 40 ° C, and a carbohydrate monophosphine borane adduct can be obtained, in which case R 4 and R 5 are not OH or SH.
在具有通式IX或通式X的环氧化物分别与MPR 4R 5[M＝Li，Na，K，MgX 1(X 1＝Cl，Br，I)]在-40℃到50℃温度范围内反应后，未加入质子酸(如甲醇、乙醇、水)之前，可先加入1到5当量的BH 3的四氢呋喃或二甲硫醚加合物在-40℃到50℃温度范围内反应，再加入质子酸，得到碳水化合物单膦的硼烷加合物。 The epoxides of general formula IX or general formula X and MPR 4 R 5 [M = Li, Na, K, MgX 1 (X 1 = Cl, Br, I)] in the temperature range of -40 ℃ to 50 ℃ After the internal reaction, before adding protonic acid (such as methanol, ethanol, water), you can first add 1 to 5 equivalents of BH 3 in tetrahydrofuran or dimethyl sulfide adduct to react in the temperature range of -40 ℃ to 50 ℃, Protonic acid is then added to obtain the borane adduct of carbohydrate monophosphine.
在碳水化合物单膦(通式为Ia、Ib或它们的混合物，或IIa、IIb或它们的混合物)及其硼烷加合物(通式为Va、Vb或它们的混合物，或VIa、VIb或它们的混合物)中，当R 4或R 5之一为H且R 6也为H时，在碱作用下(后)，如用KH、NaH、叔丁醇钾或叔丁醇钠，再与X 2(C1-C6)烷基卤代物或X 2CH 2(C6-C10)芳亚甲基卤(磺酸酯)代物，这里X 2为Cl、Br、I、磺酸基或硫酸基，获得R 4或R 5之一和R 6同为(C1-C6)烷基、-CH 2(C6-C10)芳亚甲基的碳水化合物单膦或其硼烷加合物；当R 4或R 5之一为H且R 6也为H时，在KH、NaH、叔丁醇钾或叔丁醇钠碱的作用下，再通过控制加入X 2(C1-C6)烷基卤代物或X 2CH 2(C6-C10)芳亚甲基卤(磺酸酯)代物的计量比，得到R 4或R 5之一为H原子而R 6为(C1-C6)烷基或-CH 2(C6-C10)芳亚甲基的碳水化合物单膦或其硼烷加合物；当R 4或R 5之一为H且R 6也为H时，在正丁基锂、仲丁基锂、叔丁基锂、甲基锂或苯基锂的作用下，得到R 4或R 5之一为(C1-C6)烷基或-CH 2(C6-C10)芳亚甲基而R 6为H原子的碳水化合物单膦或其硼烷加合物；R 4或R 5之一为H的碳水化合物单膦，在钯或镍络合物的催化作用下，与卤代芳烃发生新的C-P键形成反应，得到碳水化合物三级单膦；当R 6为H时，在碱如正丁基锂、仲丁基锂、叔丁基锂、甲基锂、苯基锂、KH、NaH、叔丁醇钾、叔丁醇钠、三乙胺、二异丙胺、吡啶的作用下，再与(C1-C8)酰氯或R 9SO 2磺酰氯反应，得到R 6为(C1-C8)酰基或R 9SO 2磺酰基的碳水化合物单膦或其硼烷加合物。 In the carbohydrate monophosphine (the general formula is Ia, Ib or their mixture, or IIa, IIb or their mixture) and its borane adduct (the general formula is Va, Vb or their mixture, or VIa, VIb or Their mixture), when one of R 4 or R 5 is H and R 6 is also H, under the action of alkali (after), such as KH, NaH, potassium tert-butoxide or sodium tert-butoxide, and then X 2 (C1-C6) alkyl halide or X 2 CH 2 (C6-C10) arylmethylene halide (sulfonate) substitute, where X 2 is Cl, Br, I, sulfonate or sulfate, Obtain one of R 4 or R 5 and R 6 are (C1-C6) alkyl, -CH 2 (C6-C10) aryl methylene carbohydrate monophosphine or borane adduct; when R 4 or When one of R 5 is H and R 6 is H, under the action of KH, NaH, potassium tert-butoxide or sodium tert-butoxide, X 2 (C1-C6) alkyl halide or X is added by control 2 The ratio of CH 2 (C6-C10) arylmethylene halide (sulfonate) substitutes to obtain one of R 4 or R 5 is H atom and R 6 is (C1-C6) alkyl or -CH 2 ( C6-C10) arylmethylene carbohydrate monophosphine or its borane adduct; when one of R 4 or R 5 is H and R 6 is also H, in n-butyl lithium, sec-butyl lithium, Tert-butyl , Under the action of methyl lithium or phenyl lithium to give one of R 4 or R 5 is (C1-C6) alkyl, or -CH 2 (C6-C10) aryl and R 6 is methylene carbohydrate H atoms Monophosphine or its borane adduct; carbohydrate monophosphine with one of R 4 or R 5 being H, under the catalysis of palladium or nickel complex, a new CP bond formation reaction with halogenated aromatic hydrocarbon is obtained Carbohydrate tertiary monophosphine; when R 6 is H, in bases such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, KH, NaH, potassium tert-butoxide, tertiary Under the action of sodium butoxide, triethylamine, diisopropylamine and pyridine, and then react with (C1-C8) acid chloride or R 9 SO 2 sulfonyl chloride to obtain R 6 as (C1-C8) acyl group or R 9 SO 2 sulfonate Acyl carbohydrate monophosphine or its borane adduct.
Scheme 1Scheme1
Figure PCTCN2019088461-appb-000008
Figure PCTCN2019088461-appb-000008
在碳水化合物单膦(通式为Ia、Ib或它们的混合物和IIa、IIb或它们的混合物)中，当R 4或R 5之一为H时，可被O 2或S 8氧化为相应的带碳水化合物单元的二级膦氧化物或二级膦硫化物。 In the carbohydrate monophosphine (the general formula is Ia, Ib or their mixture and IIa, IIb or their mixture), when one of R 4 or R 5 is H, it can be oxidized by O 2 or S 8 to the corresponding Secondary phosphine oxide or secondary phosphine sulfide with carbohydrate units.
在碳水化合物单膦(通式为Ia、Ib或它们的混合物和IIa、IIb或它们的混合物)中，当R 4或R 5均不为H、OH或SH时，此时它们为三级膦可被O 2、S 8或Se氧化为相应的通式为VII和VIII带碳水化合物单元的三级膦氧化物、硫化物或硒化物。 In carbohydrate monophosphines (general formula Ia, Ib or their mixtures and IIa, IIb or their mixtures), when neither R 4 or R 5 is H, OH or SH, they are tertiary phosphines It can be oxidized by O 2 , S 8 or Se to corresponding tertiary phosphine oxides, sulfides or selenides with carbohydrate units of general formula VII and VIII.
碳水化合物单膦、及其硼烷加合物或膦氧化物、硫化物或硒化物，可以通过重结晶或普通硅胶柱层析分离纯化，得到光学纯度为≥95％的通式为Ia、Ib、IIa和IIb碳水化合物单膦，或光学纯度为≥95％的通式为IIIa、IIIb、IVa和IVb碳水化合物单膦的硼烷加合物，或光学纯度为≥95％的通式为VIIa、VIIb、VIIIa和VIIIb碳水化合物单膦氧化物、硫化物或硒化物。当然这里描述的光学纯度为≥95％的化合物也可以通过(制备)HPLC获得，这里使用的色谱柱可以是手性的，也可以是非手性的。Carbohydrate monophosphine and its borane adduct or phosphine oxide, sulfide or selenide can be separated and purified by recrystallization or ordinary silica gel column chromatography to obtain the general formula Ia, Ib with optical purity ≥95% , IIa and IIb carbohydrate monophosphines, or borane adducts of general formula IIIa, IIIb, IVa and IVb carbohydrate monophosphines with optical purity ≥95%, or general formula VIIa with optical purity ≥95% , VIIb, VIIIa and VIIIb carbohydrate monophosphine oxides, sulfides or selenides. Of course, the compounds described herein with an optical purity of ≥95% can also be obtained by (preparative) HPLC, and the chromatographic column used here can be chiral or achiral.
第二十三方面，本发明提供了上面描述的碳水化合物单膦硼烷加合物(通式为Va、Vb或它们的混合物和VIa、VIb或它们的混合物)的脱硼烷的方法。碳水化合物单膦硼烷加合物在20℃到150℃温度范围内，优选温度为50℃到130℃温度，与过量的二乙胺、二异丙胺、吗啡啉、三乙烯二胺(DABCO)、甲醇、乙醇、丙醇、丁醇、水或它们的混合物反应，可以高效地脱除硼烷得到碳水化合物单膦。In a twenty-third aspect, the present invention provides a method for deboration of the above-described carbohydrate monophosphine borane adduct (the general formula is Va, Vb or a mixture thereof and VIa, VIb or a mixture thereof). Carbohydrate monophosphine borane adduct in the temperature range of 20 ℃ to 150 ℃, preferably at a temperature of 50 ℃ to 130 ℃, with excess diethylamine, diisopropylamine, morpholine, triethylenediamine (DABCO) , Methanol, ethanol, propanol, butanol, water or a mixture of them can efficiently remove borane to obtain carbohydrate monophosphine.
第二十四方面，本发明提供了碳水化合物单膦作为支持配体与元素周期表VIII族的元素，例如钯、镍、铂、铑、铱、钌、或钴的过渡金属络合物或过渡金属盐的组合用作催化剂。通常，本发明提供的碳水化合物单膦可以加入到合适的过渡金属前体中原位地产生具有活性的催化体系。In the twenty-fourth aspect, the present invention provides a carbohydrate monophosphine as a transition metal complex or transition supporting a ligand and an element of Group VIII of the periodic table, such as palladium, nickel, platinum, rhodium, iridium, ruthenium, or cobalt The combination of metal salts is used as a catalyst. Generally, the carbohydrate monophosphine provided by the present invention can be added to a suitable transition metal precursor to generate an active catalytic system in situ.
第二十五方面，本发明提供了一系列碳水化合物单膦配位的钯络合物，具有通式XI、XII、XIII、XIV或XV：In the twenty-fifth aspect, the present invention provides a series of carbohydrate monophosphine coordinated palladium complexes having the general formula XI, XII, XIII, XIV or XV:
Figure PCTCN2019088461-appb-000009
Figure PCTCN2019088461-appb-000009
其中L为上面定义的碳水化合物单膦；X 3和X 7独立地选自Cl、Br或I；X 4、X 5和X 6可独立地选自Cl、Br、I、甲磺酸基、苯磺酸基、对甲苯磺酸基、甲酸基、乙酸基或苯甲酸基；R 10、R 11、R 12、R 13和R 14各自独立地选自H、甲基或苯基。 Where L is a carbohydrate monophosphine as defined above; X 3 and X 7 are independently selected from Cl, Br or I; X 4 , X 5 and X 6 can be independently selected from Cl, Br, I, mesylate, Benzenesulfonate, p-toluenesulfonate, formate, acetate or benzoate; R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from H, methyl or phenyl.
本发明还进一步提供了原位产生的钯催化体系和钯络合物在催化Suzuki-Miyaura偶联和Buchwald-Hartwig胺化反应中的用途。同时，对于那些本领域技术人员来说很明显的其它过渡金属催化反应，特别是Negishi偶联、Kumada偶联、Sonagashira炔化及Heck偶联，也可使用本发明提供的催化体系。The present invention further provides the use of a palladium catalyst system and a palladium complex generated in situ to catalyze Suzuki-Miyaura coupling and Buchwald-Hartwig amination reaction. At the same time, other transition metal catalyzed reactions that are obvious to those skilled in the art, especially Negishi coupling, Kumada coupling, Sonagashira alkynylation and Heck coupling, can also use the catalytic system provided by the present invention.
可以与本发明的膦原位产生钯催化剂的钯盐或络合物有很多，包括醋酸钯、氯化钯、乙酰丙酮钯、二苯基亚甲基丙酮钯、四(三苯基膦)钯、二乙腈氯化钯、二苯腈氯化钯、烯丙基氯化钯二聚物、巴豆基氯化钯二聚物、苯丙烯基氯化钯二聚物、2-氨基联苯-2-氯化钯、1，5-环辛二烯氯化钯，或其它对于那些本领域技 术人员来说熟知的钯源。There are many palladium salts or complexes that can generate a palladium catalyst in situ with the phosphine of the present invention, including palladium acetate, palladium chloride, acetylacetone palladium, diphenylmethyleneacetone palladium, tetrakis (triphenylphosphine) palladium , Diacetonitrile palladium chloride, dibenzonitrile palladium chloride, allyl palladium chloride dimer, crotonyl palladium chloride dimer, phenylpropenyl palladium chloride dimer, 2-aminobiphenyl-2 -Palladium chloride, 1,5-cyclooctadiene palladium chloride, or other sources of palladium well known to those skilled in the art.
一般说来，利用带碳水化合物单元膦配位的钯络合物作为催化剂的前体对于催化反应应用是更为有利的，在一些情况中会缩短催化诱导期。在催化偶联反应中，本发明的钯络合物的用量相对于底物卤代芳烃比可以是0.000001到0.1当量，基于催化剂的成本和反应的可靠性，钯的用量更合适的范围选择0.0001到0.02当量。有时即使是直接应用钯络合物作为催化剂前体，也额外加入相对钯来说0.5到50倍根据本发明的带碳水化合物的单膦配体，这样一般会增加催化体系的寿命或减少钯的用量，额外加入的配体的量更多是在0.5到10倍的范围内。In general, the use of palladium complexes with phosphine coordination of carbohydrate units as the precursor of the catalyst is more advantageous for catalytic reaction applications, and in some cases will shorten the catalytic induction period. In the catalytic coupling reaction, the amount of the palladium complex of the present invention relative to the substrate halogenated aromatic hydrocarbon ratio may be 0.000001 to 0.1 equivalents. Based on the cost of the catalyst and the reliability of the reaction, the amount of palladium is more suitably selected in the range of 0.0001 To 0.02 equivalent. Sometimes even if the palladium complex is directly used as a catalyst precursor, an additional 0.5 to 50 times the carbohydrate-carrying monophosphine ligand according to the present invention is added in addition to palladium, which generally increases the life of the catalytic system or reduces the palladium The amount used, the amount of additional ligand added is more in the range of 0.5 to 10 times.
利用钯盐或络合物与带碳水化合物单元膦配体原位产生催化体系时，钯的用量可以是0.000001到0.1当量，更合适的范围选择0.00001到0.02当量。膦配体与钯的物质的量比例范围可以是100:1到1:1，一般的范围是10:1到1:1.此外，钯盐或络合物和带碳水化合物单元膦配体可以依次独立地加入到反应体系中去，也可以是钯盐或络合物和带碳水化合物单元膦配体在溶剂中先搅拌反应形成钯催化体系溶液后再加入到反应体系中去。When a palladium salt or complex is used to generate a catalytic system in situ with a phosphine ligand having a carbohydrate unit, the amount of palladium can be 0.000001 to 0.1 equivalent, and a more suitable range is selected from 0.00001 to 0.02 equivalent. The amount ratio of phosphine ligand to palladium substance can range from 100: 1 to 1: 1, and the general range is from 10: 1 to 1: 1. In addition, palladium salts or complexes and phosphine ligands with carbohydrate units can It is added to the reaction system independently in turn, or it may be that the palladium salt or complex and the phosphine ligand with carbohydrate unit are stirred and reacted in the solvent to form a palladium catalytic system solution, and then added to the reaction system.
本发明的带碳水化合物单元膦硼烷加合物需要先脱去保护基硼烷，才能与钯配位。可以通过短硅胶柱或结晶进一步提纯脱硼烷后的膦配体，一般来说利用本发明的脱硼烷方法所得到的膦配体的纯度足够高而不需要通过短硅胶柱或结晶提纯就可直接用于催化体系的制备中，这也是本发明的特点之一。因此，本发明的碳水化合物单元膦硼烷加合物具有储存方便和使用方便的优点。The phosphine borane adduct with carbohydrate unit of the present invention needs to deprotect the borane before it can coordinate with palladium. The phosphine ligand after deboration can be further purified by a short silica gel column or crystallization. Generally speaking, the purity of the phosphine ligand obtained by the deborane method of the present invention is sufficiently high without purification by a short silica gel column or crystallization. It can be directly used in the preparation of catalytic systems, which is also one of the characteristics of the present invention. Therefore, the carbohydrate unit phosphine borane adduct of the present invention has the advantages of convenient storage and convenient use.
本发明的膦配体在惰性气氛下有很好的热稳定性，因此能在高达200℃或更高的温度下使用本发明提供的催化体系。优选反应温度为0℃至180℃，甚至是20℃至140℃进行催化反应是有利的。本发明的膦还可以在加压下使用，通常压力可以到100个大气压，但优选在不高于60的大气压到常压的范围进行反应。The phosphine ligand of the present invention has good thermal stability under an inert atmosphere, and therefore can use the catalytic system provided by the present invention at a temperature as high as 200 ° C or higher. It is preferable that the reaction temperature is 0 ° C to 180 ° C, or even 20 ° C to 140 ° C to carry out the catalytic reaction. The phosphine of the present invention can also be used under pressurization, usually the pressure can be up to 100 atmospheres, but it is preferred to carry out the reaction in the range of no more than 60 atmospheres to normal pressure.
在钯催化的卤代芳烃的偶联反应中，富电子、大立体位阻的膦往往有令人惊喜的表现.由于本发明的膦是磷原子连接在碳水化合物的2-或3-位这种仲碳原子上，所以这些膦可以是富电子的一类，和具有大立体位阻的特点，这对于钯催化偶联反应的是受欢迎特征。本发明提供了多个系列的膦配体具有多种多样电子性质和立体性质不同的膦配体，这对满足各种各样的电子性质和立体性质的催 化反应的需要是极为有利的。此外值得一提的是，碳水化合物单元中带有一个或多个有利于稳定催化物种和/或提高催化活性的醚氧原子，以及碳水化合物的极性和溶解性明显有别于Buchwald等人的二联苯基膦、Hartwig等人的QPhos、Beller等人的金刚基膦、Haddad等人的1,3-氧xaphosphole膦配体及Takasago公司的带芳基环丙基骨架的膦配体，这也导致本发明的膦会具有其它膦不具备的特性。In palladium-catalyzed coupling reactions of halogenated aromatic hydrocarbons, electron-rich, large sterically hindered phosphines often have surprising performances. Since the phosphine of the present invention is a phosphorus atom connected to the 2- or 3-position of carbohydrates These are secondary carbon atoms, so these phosphines can be electron-rich and have a large steric hindrance, which is a popular feature for palladium-catalyzed coupling reactions. The present invention provides multiple series of phosphine ligands having a variety of phosphine ligands with different electronic properties and stereo properties, which is extremely advantageous for satisfying the needs of catalytic reactions of various electronic properties and stereo properties. In addition, it is worth mentioning that the carbohydrate unit contains one or more ether oxygen atoms that are conducive to stabilizing catalytic species and / or improving catalytic activity, and the polarity and solubility of carbohydrates are obviously different from those of Buchwald et al. Biphenyl phosphine, QPhos of Hartwig et al., Adamantyl phosphine of Beller et al., 1,3-oxyxaphosphole phosphine ligand of Haddad et al. And phosphine ligand with arylcyclopropyl skeleton of Takasago. It also causes the phosphines of the present invention to have characteristics not possessed by other phosphines.
以下举例说明本发明的具体实施例，而不意味着本发明仅限于以下的举例说明.The following examples illustrate specific embodiments of the present invention, does not mean that the present invention is limited to the following examples.
关键中间体碳水0化合物环氧化物，如甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(M.
Figure PCTCN2019088461-appb-000010
et al.，Organometallics 2015，34，1507-1521.)，甲基2,3-酐-4,6-氧-苯甲叉基-β-D-吡喃甘露糖苷(M.
Figure PCTCN2019088461-appb-000011
et al.，Organometallics 2015，34，1507-1521.),甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃阿洛糖苷，甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃塔罗糖苷(R.Hevey，et al.，J.Org.Chem.2012，77，6760-6772.)，甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃古罗糖苷(R.Hevey，et al.，J.Org.Chem.2012，77，6760-6772)，或甲基2,3-酐-4,6-氧-苯甲叉基-β-D-吡喃古罗糖苷(R.Hevey，et al.，J.Org.Chem.2012，77，6760-6772.)，仿照文献方法制得。 The key intermediate carbohydrate 0 compound epoxide, such as methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (M.
Figure PCTCN2019088461-appb-000010
et al., Organometallics 2015, 34, 1507-1521.), methyl 2,3-anhydride-4,6-oxo-benzylidene-β-D-mannopyranoside (M.
Figure PCTCN2019088461-appb-000011
et al., Organometallics 2015, 34, 1507-1521.), methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-allopyranoside, methyl 2,3- Anhydride-4,6-oxo-benzylidene-ɑ-D-pyrantaloside (R. Hevey, et al., J. Org. Chem. 2012, 77, 6760-6772.), Methyl 2 , 3-anhydride-4,6-oxo-benzylidene-ɑ-D-glucopyranoside (R. Hevey, et al., J. Org. Chem. 2012, 77, 6760-6772), or Methyl 2,3-anhydride-4,6-oxo-benzylidene-β-D-glucopyranoside (R. Hevey, et al., J. Org. Chem. 2012, 77, 6760-6772 .), Modeled on literature.
实施例1.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦Example 1. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -dicyclohexylphosphine
Figure PCTCN2019088461-appb-000012
Figure PCTCN2019088461-appb-000012
实施例1-1.Example 1-1.
在惰性气体保护下将二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶中,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完。回至室温,搅拌反应2小时,制得二环己基膦锂溶液。另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入二环己基膦锂溶液,搅拌反应6小时。冰水浴下加入0.5mL甲醇,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.52g白色固体,产率 76％。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL of freshly distilled tetrahydrofuran were added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane) was added dropwise at -78 ° C Solution, 10.5mmol), about 5 minutes to complete the drop. Return to room temperature and stir the reaction for 2 hours to prepare lithium dicyclohexylphosphine solution. Take another 50mL Shrek bottle, weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), and ventilate three times Inject 10mL of tetrahydrofuran with stirring and dissolve, add lithium dicyclohexylphosphine solution through a double needle tip at room temperature, and stir to react for 6 hours. Under ice-water bath, add 0.5 mL of methanol, remove the solvent under reduced pressure, add 15 mL of dichloromethane to dissolve the residue, wash with saturated ammonium chloride solution, dry with anhydrous Na 2 SO 4 , and remove the solvent under reduced pressure. Recrystallization, to obtain 3.52g white solid, yield 76%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-2.92。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-2.92.
实施例1-2.Example 1-2.
在惰性气体保护下,于50mL史莱克瓶中称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol)和叔丁醇钾(1.11g10.0mmol),抽换气三次,注入无水脱氧的DMSO(10mL)和二环己基膦(2.0mL,10.0mmol),80℃反应搅拌反应2小时。减压下抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,有机相用无水Na 2SO 4干燥,减压抽除溶剂,再用甲醇重结晶,得到3.78g白色泡沫状固体,产率82％。 Under the protection of inert gas, in a 50mL Shrek bottle, weigh methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol) and tertiary Potassium butoxide (1.11g10.0mmol) was pumped and ventilated three times. Anhydrous deoxygenated DMSO (10mL) and dicyclohexylphosphine (2.0mL, 10.0mmol) were injected and the reaction was stirred at 80 ° C for 2 hours. The solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, the solution was washed with saturated ammonium chloride, the organic phase was dried over anhydrous Na 2 SO 4 , the solvent was removed under reduced pressure, and then recrystallized from methanol to obtain 3.78g white foamy solid, yield 82%.
实施例1-3.Examples 1-3.
在惰性气体保护下量取二环己基氯化膦(2.2mL,10.0mmol),冰水浴冷却至0℃,加入10mL新蒸四氢呋喃.剪入金属锂(140mg,20mmol),室温下搅拌反应24h,制得二环己基膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,有机相用无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到4.16g白色泡沫状固体,产率90％。 Measure dicyclohexylphosphine chloride (2.2mL, 10.0mmol) under inert gas protection, cool to 0 ° C in an ice water bath, add 10mL of freshly distilled tetrahydrofuran. Cut in lithium metal (140mg, 20mmol), and stir at room temperature for 24h, A lithium dicyclohexylphosphine solution was prepared. Another 50mL Shrek bottle was weighed into methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, adding lithium dicyclohexylphosphine solution through a double needle tip, stirring and reacting for 6 hours. Add 0.5mL of methanol under ice water bath, remove the solvent under reduced pressure, add 15mL of methylene chloride The residue was dissolved, and the solution was washed with saturated ammonium chloride. The organic phase was dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 4.16 g of white foamy solid with a yield of 90%. .
实施例2.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 2. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000013
Figure PCTCN2019088461-appb-000013
在惰性气体保护下称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦(4.6g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后继续搅拌3小时.减压抽去溶剂,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,经过短硅胶柱提纯,得到4.7g白色泡沫状固体,产率98％.mp:169.4～172.0℃。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azetosyl-3) -dicyclohexylphosphine (4.6g, 10mmol) under inert gas protection, A solution of borane in tetrahydrofuran (1.0 M, 11 mL, 11 mmol) was added dropwise at -20 ° C, and after returning to room temperature, stirring was continued for 3 hours. The solvent was removed under reduced pressure, and 0.5 mL of methanol was added to the residue, followed by 15 mL of dichloromethane Methane is dissolved and purified through a short silica gel column to obtain 4.7 g of white foamy solid with a yield of 98%. Mp: 169.4-172.0 ° C.
1H NMR(400MHz,CDCl 3)δ7.48–7.31(m,5H),5.56(s,1H),4.63(s,1H),4.54(d,J＝7.2Hz,1H),4.42(ddd,J＝18.0,9.9,7.8Hz,1H),4.36–4.28(m,1H),3.89(td,J＝10.1,5.0Hz,1H),3.74(t,J＝10.1Hz,1H),3.44(s,3H),2.75(ddd,J＝10.4,7.7, 2.4Hz,1H),2.63(dd,J＝24.6,12.3Hz,1H),2.35(d,J＝10.4Hz,1H),2.24(dt,J＝20.1,10.0Hz,1H),2.17(d,J＝11.5Hz,1H),1.87–0.79(m,18H),0.31(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48–7.31 (m, 5H), 5.56 (s, 1H), 4.63 (s, 1H), 4.54 (d, J = 7.2 Hz, 1H), 4.42 (ddd, J = 18.0, 9.9, 7.8Hz, 1H), 4.36-4.28 (m, 1H), 3.89 (td, J = 10.1, 5.0Hz, 1H), 3.74 (t, J = 10.1Hz, 1H), 3.44 (s , 3H), 2.75 (ddd, J = 10.4, 7.7, 2.4Hz, 1H), 2.63 (dd, J = 24.6, 12.3Hz, 1H), 2.35 (d, J = 10.4Hz, 1H), 2.24 (dt, J = 20.1, 10.0 Hz, 1H), 2.17 (d, J = 11.5 Hz, 1H), 1.87-0.79 (m, 18H), 0.31 (br, 3H).
31P{ 1H}NMR(162MHz,CDCl 3)δ33.61。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 33.61.
实施例3.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 3. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000014
Figure PCTCN2019088461-appb-000014
实施例3-1.Example 3-1.
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(1.0g,2.1mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,80mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.13mL,2.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.0g白色固体,产率93％。mp:197.4～198.1℃。
Figure PCTCN2019088461-appb-000015
(c 0.3,CH 2Cl 2)。 Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (1.0g, 2.1mmol) in In a 50mL Shrek bottle, ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NaH (60% kerosene mixture, 80mg) under an inert gas atmosphere, stir for 1 hour, use ice / The sodium chloride system was cooled to -10 ° C, iodomethane (0.13 mL, 2.0 mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20 mL of dichloromethane, then filtered through celite, silica gel Separation and purification by column chromatography gave 1.0 g of white solid with a yield of 93%. mp: 197.4 ～ 198.1 ℃.
Figure PCTCN2019088461-appb-000015
(c 0.3, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.47–7.42(m,2H),7.41–7.35(m,3H),5.55(s,1H),4.66(s,1H),4.34(ddd,J＝20.0,10.1,7.3Hz,2H),4.31(dd,J＝10.3,4.9Hz,1H),4.10(d,J＝6.5Hz,1H),3.85(td,J＝10.0,4.9Hz,1H),3.74(t,J＝10.2Hz,1H),3.43(s,3H),3.42(s,3H),2.85(dd,J＝12.2,7.3Hz,1H),2.79–2.67(m,1H),1.89–1.51(m,10H),1.46–1.10(m,8H),1.08–0.95(m,1H),0.94–0.83(m,1H),0.41(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.47–7.42 (m, 2H), 7.41–7.35 (m, 3H), 5.55 (s, 1H), 4.66 (s, 1H), 4.34 (ddd, J = 20.0 , 10.1, 7.3Hz, 2H), 4.31 (dd, J = 10.3, 4.9Hz, 1H), 4.10 (d, J = 6.5Hz, 1H), 3.85 (td, J = 10.0, 4.9Hz, 1H), 3.74 (t, J = 10.2 Hz, 1H), 3.43 (s, 3H), 3.42 (s, 3H), 2.85 (dd, J = 12.2, 7.3 Hz, 1H), 2.79–2.67 (m, 1H), 1.89– 1.51 (m, 10H), 1.46–1.10 (m, 8H), 1.08–0.95 (m, 1H), 0.94–0.83 (m, 1H), 0.41 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.25,129.12,128.21,126.02,102.53,98.92,77.91,77.84,77.37,77.29,69.83,60.46,57.62,54.27,34.26,34.05,31.48,31.21,31.16,30.41,30.39,28.75,28.62,27.84,27.78,27.76,27.67,26.81,26.68,26.61,26.54,26.52,26.23,26.22,25.88,25.87。 13 C NMR (101 MHz, CDCl 3 ) δ 137.25, 129.12, 128.21, 126.02, 102.53, 98.92, 77.91, 77.84, 77.37, 77.29, 69.83, 60.46, 57.62, 54.27, 34.26, 34.05, 31.48, 31.21, 31.16, 30.41, 30.39 , 28.75, 28.62, 27.84, 27.78, 27.76, 27.67, 26.81,26.68, 26.61,26.54, 26.52, 26.23, 26.22, 25.88, 25.87.
13C NMR(101MHz,CDCl 3)δ137.25(s),129.11(s),128.21(s),126.02(s),102.54(s),98.92(s),77.88(d,J＝6.8Hz),77.32(d,J＝5.9Hz),69.83(s),60.45(s),57.62(s),54.27(s),34.16(d,J＝21.0Hz),32.12–22.43(m)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.25 (s), 129.11 (s), 128.21 (s), 126.02 (s), 102.54 (s), 98.92 (s), 77.88 (d, J = 6.8Hz) , 77.32 (d, J = 5.9 Hz), 69.83 (s), 60.45 (s), 57.62 (s), 54.27 (s), 34.16 (d, J = 21.0 Hz), 32.12-22.43 (m).
31P{ 1H}NMR(162MHz,CDCl 3)δ34.09。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 34.09.
实施例3-2.Example 3-2.
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(1.0g,2.1mmol)置于50mL组合式史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,100mg)搅拌1小时后,加入硫酸二甲酯(0.2mL,2.1mmol),于60℃下搅拌反应24小时,减压抽除溶剂,残余物用20mL二氯甲烷溶解经硅藻土过滤,硅胶柱层析分离提纯,得到0.9g白色固体,产率92％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (1.0g, 2.1mmol) in In a 50mL combined Shrek bottle, ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NaH (60% kerosene mixture, 100mg) under an inert gas atmosphere, stir for 1 hour, add Dimethyl sulfate (0.2 mL, 2.1 mmol) was stirred at 60 ° C for 24 hours. The solvent was removed under reduced pressure. The residue was dissolved in 20 mL of dichloromethane, filtered through celite, and purified by silica gel column chromatography to obtain 0.9 g white solid, yield 92%.
实施例4.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦Example 4. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine
Figure PCTCN2019088461-appb-000016
Figure PCTCN2019088461-appb-000016
实施例4-1.Example 4-1.
称取(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(500mg,1.02mmol)置于史莱克瓶中,抽换气三次,注入0.2mL已脱氧的吗啡啉和5mL乙醇,油浴80℃加热搅拌3小时.减压抽除溶剂,剩余油状物经短的硅胶柱提纯,得到484mg白色固体,产率98％。Weigh (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine-borane (500mg , 1.02mmol) placed in a Shrek bottle, pumping and ventilating three times, injecting 0.2mL of deoxygenated morpholine and 5mL of ethanol, heating and stirring in an oil bath at 80 ℃ for 3 hours. The solvent was removed under reduced pressure, the remaining oil was passed through a short silica gel Column purification gave 484 mg of white solid in 98% yield.
1H NMR(400MHz,CDCl 3)δ7.41(d,J＝68.6Hz,5H),5.55(s,1H),4.65(s,1H),4.50(d,J＝0.5Hz,1H),4.29(dd,J＝14.0,8.3Hz,2H),3.98–3.69(m,2H),3.43(d,J＝22.2Hz,7H),3.05(s,1H),2.25–0.78(m,20H),0.64(dd,J＝33.8,22.2Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 68.6 Hz, 5H), 5.55 (s, 1H), 4.65 (s, 1H), 4.50 (d, J = 0.5 Hz, 1H), 4.29 (dd, J = 14.0, 8.3 Hz, 2H), 3.98–3.69 (m, 2H), 3.43 (d, J = 22.2 Hz, 7H), 3.05 (s, 1H), 2.25–0.78 (m, 20H), 0.64 (dd, J = 33.8, 22.2 Hz, 1H).
13C NMR(101MHz,CDCl 3)δ137.56(s),128.79(s),127.87(s),126.65(s),102.23(s),98.90(s),79.16(s),77.17(s),69.17(s),65.42(s),60.43(d,J＝12.4Hz),57.80(s),54.88(s),33.71(d,J＝16.7Hz),32.19(t,J＝23.1Hz),31.30(s),31.02(d,J＝12.2Hz),29.67–29.03(m),29.03–27.50(m),26.62(s),25.87(s)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.56 (s), 128.79 (s), 127.87 (s), 126.65 (s), 102.23 (s), 98.90 (s), 79.16 (s), 77.17 (s) , 69.17 (s), 65.42 (s), 60.43 (d, J = 12.4 Hz), 57.80 (s), 54.88 (s), 33.71 (d, J = 16.7 Hz), 32.19 (t, J = 23.1 Hz) , 31.30 (s), 31.02 (d, J = 12.2 Hz), 29.67-29.03 (m), 29.03-27.50 (m), 26.62 (s), 25.87 (s).
31P{ 1H}NMR(162MHz,CDCl 3)δ-3.39。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-3.39.
实施例4-2.Example 4-2.
称取(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(500mg,1.02mmol)置于史莱克瓶中,抽换气三次,注入0.2mL已脱氧的二乙胺和5mL乙醇,油浴80℃加热搅拌3小时.减压抽除溶剂,剩余油状物经短硅胶柱提纯,得到484mg白色固体,产率98％。Weigh (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine-borane (500mg , 1.02mmol) placed in a Shrek bottle, pumping and ventilating three times, injecting 0.2mL of deoxygenated diethylamine and 5mL of ethanol, heating and stirring in an oil bath at 80 ℃ for 3 hours. The solvent was removed under reduced pressure, and the remaining oil was passed through a short silica gel Column purification gave 484 mg of white solid in 98% yield.
实施例5.(甲基2-氧-乙酰基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 5. (Methyl 2-oxo-acetyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000017
Figure PCTCN2019088461-appb-000017
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(238mg,0.5mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,80mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,氮气保护下加入乙酰氯(65uL,0.6mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到230mg白色固体,产率88％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (238 mg, 0.5 mmol) in 50 mL In a Shrek bottle, ventilate three times, inject 10 mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NɑH (60% kerosene mixture, 80 mg) under an inert gas atmosphere, stir for 1 hour, and use ice / chlorine The sodium hydroxide system was cooled to -10 ° C, acetyl chloride (65uL, 0.6mmol) was added under nitrogen protection, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20mL of dichloromethane, then filtered through celite, silica gel Separation and purification by column chromatography gave 230 mg of white solid with a yield of 88%.
1H NMR(400MHz,CDCl 3)δ＝7.50(dd,J＝6.5Hz,2.9,2H),7.42–7.35(m,3H),5.60(s,1H),5.54(d,J＝6.7Hz,1H),4.63(s,1H),4.41–4.31(m,2H),4.11(td,J＝10.2,5.1Hz,1H),3.74(t,J＝10.2Hz,1H),3.45(s,3H),2.82(dd,J＝12.8,6.9Hz,1H),2.57(q,J＝12.0Hz,1H),2.39(d,J＝12.0Hz,1H),2.30–2.19(m,2H),2.15(s,3H),1.91–1.71(m,6H),1.71–1.48(m,3H),1.44–1.34(m,1H),1.34–1.09(m,7H),1.09–0.94(m,1H),0.49(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ = 7.50 (dd, J = 6.5 Hz, 2.9, 2H), 7.42-7.35 (m, 3H), 5.60 (s, 1H), 5.54 (d, J = 6.7 Hz, 1H), 4.63 (s, 1H), 4.41-4.31 (m, 2H), 4.11 (td, J = 10.2, 5.1 Hz, 1H), 3.74 (t, J = 10.2 Hz, 1H), 3.45 (s, 3H ), 2.82 (dd, J = 12.8, 6.9 Hz, 1H), 2.57 (q, J = 12.0 Hz, 1H), 2.39 (d, J = 12.0 Hz, 1H), 2.30–2.19 (m, 2H), 2.15 (s, 3H), 1.91–1.71 (m, 6H), 1.71–1.48 (m, 3H), 1.44–1.34 (m, 1H), 1.34–1.09 (m, 7H), 1.09–0.94 (m, 1H) , 0.49 (br, 3H).
13C NMR(101MHz,CDCl 3)δ169.36(s),137.09(s),129.21(s),128.21(s),126.20(s),102.65(s),97.58(s),76.83(d,J＝5.9Hz),70.85(d,J＝7.6Hz),69.68(s),60.26(s),54.48(s),34.52(d,J＝21.1Hz),32.63–25.53(m),21.16(s)。 13 C NMR (101 MHz, CDCl 3 ) δ 169.36 (s), 137.09 (s), 129.21 (s), 128.21 (s), 126.20 (s), 102.65 (s), 97.58 (s), 76.83 (d, J = 5.9Hz), 70.85 (d, J = 7.6Hz), 69.68 (s), 60.26 (s), 54.48 (s), 34.52 (d, J = 21.1Hz), 32.63-25.53 (m), 21.16 ( s).
31P{ 1H}NMR(162MHz,CDCl 3)δ34.92。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 34.92.
实施例6.(甲基2-氧-苯甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 6. (Methyl 2-oxo-benzyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine-boron alkyl
Figure PCTCN2019088461-appb-000018
Figure PCTCN2019088461-appb-000018
称取二环己基膦-硼烷(4.7g,10.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加苄氯(1.15mL,10.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20 mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到5.4g白色固体,产率98％。Weigh dicyclohexylphosphine-borane (4.7g, 10.0mmol) in a 50mL Shrek bottle, pump and ventilate three times, inject 10mL of anhydrous tetrahydrofuran, and cool the mixture to 0 ° C in an ice water bath, add under the protection of inert gas NɑH (60% kerosene mixture, 400 mg) was stirred for 1 hour, cooled to -10 ° C with an ice / sodium chloride system, benzyl chloride (1.15 mL, 10.0 mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure The residue was dissolved in 20 mL of dichloromethane, filtered through celite, and purified by silica gel column chromatography to obtain 5.4 g of white solid with a yield of 98%.
1H NMR(400MHz,CDCl 3)δ7.50–7.43(m,2H),7.43–7.33(m,7H),7.33–7.27(m,1H),5.56(s,1H),4.68(d,J＝12.1Hz,1H),4.63–4.55(m,2H),4.43(ddd,J＝19.9,9.9,7.2Hz,1H),4.32(dd,J＝10.2,5.0Hz,2H),3.87(td,J＝10.2,5.0Hz,1H),3.76(t,J＝10.2Hz,1H),3.37(s,3H),2.89(dd,J＝12.1,7.2Hz,1H),2.79–2.66(m,1H),2.50(s,1H),2.37–2.15(m,2H),1.84(s,2H),1.70(d,J＝8.7Hz,5H),1.62–1.50(m,2H),1.44–1.29(m,2H),1.25–0.80(m,7H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.50–7.43 (m, 2H), 7.43–7.33 (m, 7H), 7.33–7.27 (m, 1H), 5.56 (s, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.63–4.55 (m, 2H), 4.43 (ddd, J = 19.9, 9.9, 7.2 Hz, 1H), 4.32 (dd, J = 10.2, 5.0 Hz, 2H), 3.87 (td, J = 10.2, 5.0 Hz, 1H), 3.76 (t, J = 10.2 Hz, 1H), 3.37 (s, 3H), 2.89 (dd, J = 12.1, 7.2 Hz, 1H), 2.79–2.66 (m, 1H ), 2.50 (s, 1H), 2.37–2.15 (m, 2H), 1.84 (s, 2H), 1.70 (d, J = 8.7Hz, 5H), 1.62–1.50 (m, 2H), 1.44–1.29 ( m, 2H), 1.25–0.80 (m, 7H).
13C NMR(101MHz,CDCl 3)δ137.85(s),137.28(s),129.12(s),128.47(s),128.22(s),128.16(s),127.89(s),126.05(s),102.53(s),99.38(s),77.40(d,J＝6.1Hz),75.94(d,J＝6.8Hz),71.93(s),69.84(s),60.45(s),54.21(s),35.05(d,J＝20.8Hz),31.81–25.23(m)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.85 (s), 137.28 (s), 129.12 (s), 128.47 (s), 128.22 (s), 128.16 (s), 127.89 (s), 126.05 (s) , 102.53 (s), 99.38 (s), 77.40 (d, J = 6.1Hz), 75.94 (d, J = 6.8Hz), 71.93 (s), 69.84 (s), 60.45 (s), 54.21 (s) , 35.05 (d, J = 20.8 Hz), 31.81-25.23 (m).
31P{ 1H}NMR(162MHz,CDCl 3)δ34.01。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 34.01.
HRMS(ESI)理论值C 33H 42BO 5P+H +:561.2941.实测值:561.2786。 HRMS (ESI) theoretical value C 33 H 42 BO 5 P + H + : 561.2941. Found: 561.2786.
实施例7.[甲基2-氧-(4-甲基苯磺酰基)-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3]-二环己基膦-硼烷Example 7. [Methyl 2-oxo- (4-methylbenzenesulfonyl) -3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3]- Dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000019
Figure PCTCN2019088461-appb-000019
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(4.7g,10.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,氮气保护下加入对甲苯磺酰氯(1.9g,10.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到6.0g白色固体,产率96％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (4.7g, 10.0mmol) in In a 50mL Shrek bottle, ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NɑH (60% kerosene mixture, 400mg) under an inert gas atmosphere, and stir for 1 hour. The sodium chloride system was cooled to -10 ° C, p-toluenesulfonyl chloride (1.9g, 10.0mmol) was added under nitrogen protection, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20mL of dichloromethane, and then passed through diatoms The soil was filtered and purified by silica gel column chromatography to obtain 6.0g of white solid with a yield of 96%.
1H NMR(400MHz,CDCl 3)δ7.88(d,J＝8.2Hz,2H),7.47–7.31(m,7H),5.57(s,1H),5.10(d,J＝5.4Hz,1H),4.61(s,1H),4.44–4.26(m,2H),3.89(td,J＝10.1,4.9Hz,1H),3.74(t,J＝10.1Hz,1H),3.36(s,3H),2.84(dd,J＝12.4,6.9Hz,1H),2.63 –2.35(m,5H),2.15(dt,J＝11.5,10.4Hz,2H),1.69(dd,J＝44.7,31.3Hz,9H),1.50–1.35(m,1H),1.22–0.80(m,8H),0.22(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.2 Hz, 2H), 7.47–7.31 (m, 7H), 5.57 (s, 1H), 5.10 (d, J = 5.4 Hz, 1H) , 4.61 (s, 1H), 4.44-4.26 (m, 2H), 3.89 (td, J = 10.1, 4.9 Hz, 1H), 3.74 (t, J = 10.1 Hz, 1H), 3.36 (s, 3H), 2.84 (dd, J = 12.4, 6.9 Hz, 1H), 2.63-2.35 (m, 5H), 2.15 (dt, J = 11.5, 10.4 Hz, 2H), 1.69 (dd, J = 44.7, 31.3 Hz, 9H) , 1.50–1.35 (m, 1H), 1.22–0.80 (m, 8H), 0.22 (br, 3H).
13C NMR(101MHz,CDCl 3)δ145.37(s),136.96(s),132.75(s),130.12(s),129.16(s),128.45(s),128.21(s),125.97(s),102.45(s),97.84(s),77.69(d,J＝8.6Hz),76.12(d,J＝6.6Hz),69.59(s),60.53(s),54.60(s),34.82(d,J＝19.4Hz),32.42–25.18(m),21.75(s)。 13 C NMR (101 MHz, CDCl 3 ) δ 145.37 (s), 136.96 (s), 132.75 (s), 130.12 (s), 129.16 (s), 128.45 (s), 128.21 (s), 125.97 (s) , 102.45 (s), 97.84 (s), 77.69 (d, J = 8.6Hz), 76.12 (d, J = 6.6Hz), 69.59 (s), 60.53 (s), 54.60 (s), 34.82 (d, J = 19.4 Hz), 32.42-25.18 (m), 21.75 (s).
31P{ 1H}NMR(162MHz,CDCl 3)δ36.27。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 36.27.
实施例8.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦硫化物Example 8. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azepronosidyl-3) -dicyclohexylphosphine sulfide
Figure PCTCN2019088461-appb-000020
Figure PCTCN2019088461-appb-000020
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦(238mg,0.5mmol)置于25mL史莱克瓶中,抽换气三次,注入5mL氯仿,加入S 8(19mg,0.6mmol),加热回流6h.反应液冷至室温,过滤,抽除溶剂,得到254mg白色固体,产率99％。 Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine (238mg, 0.5mmol) into a 25mL Shrek bottle , the three pumping ventilation, injection 5mL chloroform was added S 8 (19mg, 0.6mmol), 6H heated to reflux. the reaction was cooled to room temperature, filtered, solvent extraction, to give 254mg white solid, yield 99%.
1H NMR(400MHz,CDCl 3)δ7.42(m,5H),5.57(s,1H),4.69(s,1H),4.50(d,J＝8.9Hz,1H),4.42–4.21(m,2H),3.82–3.71(m,2H),3.42(d,J＝9.8Hz,6H),2.94(dd,J＝17.4,7.5Hz,1H),2.83–2.19(m,4H),1.97–1.49(m,10H),1.29–0.84(m,8H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (m, 5H), 5.57 (s, 1H), 4.69 (s, 1H), 4.50 (d, J = 8.9 Hz, 1H), 4.42-4.21 (m, 2H), 3.82–3.71 (m, 2H), 3.42 (d, J = 9.8Hz, 6H), 2.94 (dd, J = 17.4, 7.5Hz, 1H), 2.83–2.19 (m, 4H), 1.97–1.49 (m, 10H), 1.29–0.84 (m, 8H).
13C NMR(101MHz,CDCl 3)δ137.09(s),129.17(s),128.23(s),125.96(s),102.61(s),98.90(s),77.64(d,J＝3.9Hz),77.33(d,J＝5.5Hz),71.44–65.87(m),60.01(s),57.29(s),54.26(s),41.05(d,J＝35.0Hz),38.18–24.17(m)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.09 (s), 129.17 (s), 128.23 (s), 125.96 (s), 102.61 (s), 98.90 (s), 77.64 (d, J = 3.9Hz) , 77.33 (d, J = 5.5 Hz), 71.44-65.87 (m), 60.01 (s), 57.29 (s), 54.26 (s), 41.05 (d, J = 35.0 Hz), 38.18-24.17 (m).
31P{ 1H}NMR(162MHz,CDCl 3)δ67.71。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 67.71.
实施例9.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦硒化物Example 9. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine selenide
Figure PCTCN2019088461-appb-000021
Figure PCTCN2019088461-appb-000021
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦(238 mg,0.5mmol)置于25mL史莱克瓶中,抽换气三次,注入5mL氯仿,加入硒粉(23.7mg,0.6mmol),加热回流6h.反应液冷至室温,过滤,抽除溶剂,得到278mg白色固体,产率99％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine (238 mg, 0.5 mmol) in 25 mL Shrek The bottle was ventilated three times, 5 mL of chloroform was injected, selenium powder (23.7 mg, 0.6 mmol) was added, and heated to reflux for 6 h. The reaction solution was cooled to room temperature, filtered, and the solvent was removed to obtain 278 mg of white solid with a yield of 99%.
1H NMR(400MHz,CDCl 3)δ7.54–7.34(m,5H),5.57(s,1H),4.76–4.61(m,2H),4.42–4.24(m,2H),3.88–3.66(m,2H),3.43(d,J＝20.2Hz,6H),2.94(dd,J＝16.6,7.4Hz,1H),2.87–2.31(m,4H),1.97–1.46(m,10H),1.31–0.97(m,8H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.54–7.34 (m, 5H), 5.57 (s, 1H), 4.76–4.61 (m, 2H), 4.42–4.24 (m, 2H), 3.88–3.66 (m , 2H), 3.43 (d, J = 20.2 Hz, 6H), 2.94 (dd, J = 16.6, 7.4 Hz, 1H), 2.87–2.31 (m, 4H), 1.97–1.46 (m, 10H), 1.31– 0.97 (m, 8H).
13C NMR(101MHz,CDCl 3)δ137.05(s),129.23(s),128.25(s),125.98(s),102.70(s),98.91(s),78.67(d,J＝4.9Hz),77.90(d,J＝6.5Hz),69.75(s),59.97(s),57.19(s),54.27(s),40.60(d,J＝27.9Hz),36.45–25.02(m)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.05 (s), 129.23 (s), 128.25 (s), 125.98 (s), 102.70 (s), 98.91 (s), 78.67 (d, J = 4.9Hz) , 77.90 (d, J = 6.5 Hz), 69.75 (s), 59.97 (s), 57.19 (s), 54.27 (s), 40.60 (d, J = 27.9 Hz), 36.45-25.02 (m).
31P{ 1H}NMR(162MHz,CDCl 3)δ65.43。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 65.43.
实施例10.甲基3-脱氧-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 10. Methyl 3-deoxy-ɑ-D-pyranopyranosidyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000022
Figure PCTCN2019088461-appb-000022
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(1.0g,2.1mmol)置于50mL两口瓶中,注入3.0mL THF溶解后,再注入5.0mL的5％的高氯酸水溶液搅拌过夜.抽除溶剂得到粘稠状固体。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (1.0g, 2.1mmol) in Into a 50mL two-necked bottle, inject 3.0mL of THF to dissolve, then inject 5.0mL of 5% perchloric acid aqueous solution and stir overnight. The solvent was removed to obtain a viscous solid.
31P{ 1H}NMR(162MHz,CDCl 3)δ29.98。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 29.98.
实施例11.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦Example 11. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -di-tert-butylphosphine
Figure PCTCN2019088461-appb-000023
Figure PCTCN2019088461-appb-000023
在惰性气体保护下中量取二叔丁基膦(1.85mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶中,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温搅拌反应12小时,制得二叔丁基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入二叔丁基膦锂溶液,搅拌反应24小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤分离出有机相,用无水Nɑ 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结 晶,得到2.3g白色固体,产率61％。 Under the protection of inert gas, di-tert-butylphosphine (1.85mL, 10.0mmol) and 10mL of freshly distilled tetrahydrofuran were added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M N-hexane solution, 10.5 mmol), after about 5 minutes of dripping, return to room temperature and stir for 12 hours to prepare lithium di-tert-butylphosphonate solution. Take another 50mL Shrek bottle and weigh into methyl 2,3-anhydride -4,6-Oxyl-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, adding lithium di-tert-butylphosphonate solution through the double needle tip , Stir the reaction for 24 hours. Add 0.5 mL of methanol under ice-water bath, stir for half an hour, remove the solvent under reduced pressure, add 15 mL of dichloromethane to dissolve the residue, then wash the solution with saturated ammonium chloride to separate the organic phase, use anhydrous Nɑ 2 SO 4 was dried and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 2.3 g of white solid with a yield of 61%.
31P{ 1H}NMR(162MHz,CDCl 3)δ47.32。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 47.32.
实施例12.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷Example 12. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -di-tert-butylphosphine-borane
Figure PCTCN2019088461-appb-000024
Figure PCTCN2019088461-appb-000024
在惰性气体保护下称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基基膦(4.1g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后搅拌3小时.减压抽去溶剂以及多余的硼烷,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,经过短硅胶柱提纯,得到4.2g白色泡沫状固体,产率99％。mp:73.7～74.9℃。Under the protection of inert gas, weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -di-tert-butylphosphine (4.1g, 10mmol ), Add a solution of borane in tetrahydrofuran (1.0M, 11mL, 11mmol) dropwise at -20 ° C, return to room temperature and stir for 3 hours. Remove the solvent and excess borane under reduced pressure, and add 0.5mL of methanol to the residue. Then add 15mL of dichloromethane to dissolve and purify through a short silica gel column to obtain 4.2g of white foamy solid with a yield of 99%. mp: 73.7 ～ 74.9 ℃.
1H NMR(400MHz,CDCl 3)δ7.37(d,J＝13.7Hz,5H),5.46(s,1H),4.58(d,J＝5.0Hz,1H),4.42(ddd,J＝15.4,12.3,6.8Hz,2H),4.22–4.08(m,1H),4.00(td,J＝9.6,4.7Hz,1H),3.68(t,J＝10.1Hz,1H),3.47(s,3H),2.88(dd,J＝19.7,9.9Hz,1H),1.22(dd,J＝13.4,9.6Hz,18H),0.46(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 13.7 Hz, 5H), 5.46 (s, 1H), 4.58 (d, J = 5.0 Hz, 1H), 4.42 (ddd, J = 15.4, 12.3, 6.8Hz, 2H), 4.22-4.08 (m, 1H), 4.00 (td, J = 9.6, 4.7Hz, 1H), 3.68 (t, J = 10.1Hz, 1H), 3.47 (s, 3H), 2.88 (dd, J = 19.7, 9.9 Hz, 1H), 1.22 (dd, J = 13.4, 9.6 Hz, 18H), 0.46 (br, 3H).
13C NMR(101MHz,CDCl 3)δ136.69(s),129.18(s),128.11(s),126.51(s),103.20(s),99.26(s),78.81(s),60.55(s),57.69(s),54.17(s),37.92(d,J＝9.6Hz),35.25(s),34.99(s),34.65(d,J＝19.7Hz),30.00(s),29.63(d,J＝14.2Hz)。 13 C NMR (101 MHz, CDCl 3 ) δ 136.69 (s), 129.18 (s), 128.11 (s), 126.51 (s), 103.20 (s), 99.26 (s), 78.81 (s), 60.55 (s) , 57.69 (s), 54.17 (s), 37.92 (d, J = 9.6Hz), 35.25 (s), 34.99 (s), 34.65 (d, J = 19.7Hz), 30.00 (s), 29.63 (d, J = 14.2 Hz).
31P{ 1H}NMR(162MHz,CDCl 3)δ55.46。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 55.46.
实施例13.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷Example 13. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -di-tert-butylphosphine-boron alkyl
Figure PCTCN2019088461-appb-000025
Figure PCTCN2019088461-appb-000025
实施例13-1.Example 13-1.
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷(1.0g,2.35mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,用冰水浴冷却,于惰性气体保护下加入NɑH(60％的煤油混合物,100mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.26mL,4.0mmol),搅 拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.0g白色固体,产率99％.mp:116.6～117.2℃。Weigh out (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -di-tert-butylphosphine-borane (1.0g, 2.35mmol) In a 50mL Shrek bottle, pump and ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool with an ice water bath, add NɑH (60% kerosene mixture, 100mg) under an inert gas atmosphere, stir for 1 hour, and use ice / sodium chloride The system was cooled to -10 ° C, methyl iodide (0.26mL, 4.0mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, the residue was dissolved with 20mL of dichloromethane, and then filtered through celite, silica gel column chromatography Separation and purification, to obtain 1.0g white solid, yield 99%. Mp: 116.6 ~ 117.2 ℃.
Figure PCTCN2019088461-appb-000026
(c 2.0,CH 2Cl 2)。
Figure PCTCN2019088461-appb-000026
(c 2.0, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.45–7.39(m,2H),7.36–7.30(m,3H),5.59(s,1H),4.65(s,1H),4.43(d,J＝8.7Hz,1H),4.34(ddd,J＝11.9,9.4,6.5Hz,1H),4.34(d,J＝10.7Hz,1H),4.05(td,J＝10.0,5.1Hz,1H),3.74(t,J＝10.3Hz,1H),3.47(s,3H),3.36(s,3H),3.06(dd,J＝15.0,8.8Hz,1H),1.38(d,J＝13.9Hz,9H),1.19(d,J＝12.6Hz,9H),0.58(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.45–7.39 (m, 2H), 7.36–7.30 (m, 3H), 5.59 (s, 1H), 4.65 (s, 1H), 4.43 (d, J = 8.7 Hz, 1H), 4.34 (ddd, J = 11.9, 9.4, 6.5 Hz, 1H), 4.34 (d, J = 10.7 Hz, 1H), 4.05 (td, J = 10.0, 5.1 Hz, 1H), 3.74 (t , J = 10.3 Hz, 1H), 3.47 (s, 3H), 3.36 (s, 3H), 3.06 (dd, J = 15.0, 8.8 Hz, 1H), 1.38 (d, J = 13.9 Hz, 9H), 1.19 (d, J = 12.6 Hz, 9H), 0.58 (br, 3H).
13C NMR(101MHz,CDCl 3)δ136.69(s),129.18(s),128.11(s),126.51(s),103.20(s),99.25(d,J＝1.8Hz),78.78(d,J＝6.4Hz),76.63(d,J＝7.9Hz),70.05(s),60.55(s),57.81(s),54.17(s),37.92(d,J＝9.6Hz),35.25(s),34.99(s),34.65(d,J＝19.7Hz),30.01(d,J＝2.6Hz),29.56(d,J＝0.6Hz)。 13 C NMR (101 MHz, CDCl 3 ) δ 136.69 (s), 129.18 (s), 128.11 (s), 126.51 (s), 103.20 (s), 99.25 (d, J = 1.8 Hz), 78.78 (d, J = 6.4 Hz), 76.63 (d, J = 7.9 Hz), 70.05 (s), 60.55 (s), 57.81 (s), 54.17 (s), 37.92 (d, J = 9.6 Hz), 35.25 (s) , 34.99 (s), 34.65 (d, J = 19.7 Hz), 30.01 (d, J = 2.6 Hz), 29.56 (d, J = 0.6 Hz).
31P{ 1H}NMR(162MHz,CDCl 3)δ64.13。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 64.13.
实施例13-2.Example 13-2.
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷(1.00g,2.35mmol)置于50mL组合式史莱克瓶中,抽换气三次,加入4mL 1M NaOH水溶液和10mL四氢呋喃,加入硫酸二甲酯(0.2mL,2.1mmol),80℃下反应1小时后,再加入4mL 1M NaOH水溶液搅拌反应1小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,经硅胶柱层析分离提纯,得到0.90g白色固体,产率87％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -di-tert-butylphosphine-borane (1.00 g, 2.35 mmol) In a 50mL combined Shrek bottle, evacuate three times, add 4mL of 1M NaOH aqueous solution and 10mL of tetrahydrofuran, add dimethyl sulfate (0.2mL, 2.1mmol), and react at 80 ℃ for 1 hour, then add 4mL of 1M NaOH aqueous solution The reaction was stirred for 1 hour. The solvent was removed under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, and purified by silica gel column chromatography to obtain 0.90 g of white solid with a yield of 87%.
实施例14.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦Example 14. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -di-tert-butylphosphine
Figure PCTCN2019088461-appb-000027
Figure PCTCN2019088461-appb-000027
实施例14-1.Example 14-1.
将500mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷(1.15mmol)置于0.2mL已脱氧的吗啡啉和5mL的乙醇中,油浴80℃加热搅拌至TLC跟踪反应完全,将温度降至室温,抽去吗啡啉和溶剂,剩余油状物经短硅胶柱提纯,得到431mg白色固体,产率89％。500mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azepronosidyl-3) -di-tert-butylphosphine-borane (1.15mmol) placed in 0.2mL of deoxygenated morpholine and 5mL of ethanol, heated and stirred in an oil bath at 80 ℃ until the TLC tracking reaction was complete, the temperature was reduced to room temperature, morphine and solvent were pumped out, the remaining oil was passed through a short silica Column purification gave 431 mg of white solid in 89% yield.
31P{ 1H}NMR(162MHz,CDCl 3)δ52.03。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 52.03.
实施例14-2.Example 14-2.
将500mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二叔丁基膦-硼烷(1.15mmol)置于0.2mL脱氧的二乙胺和5mL的乙醇中,油浴80℃加热搅拌至TLC跟踪反应完全,约18h，将温度降至室温,抽去二乙胺和溶剂,剩余油状物经短硅胶柱提纯,得到445mg白色固体,产率92％。500mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azepronosidyl-3) -di-tert-butylphosphine-borane (1.15mmol) placed in 0.2mL deoxygenated diethylamine and 5mL of ethanol, heated and stirred in an oil bath at 80 ℃ until the TLC tracking reaction was complete, about 18h, the temperature was lowered to room temperature, diethylamine and solvent were removed, the remaining oil The material was purified by a short silica gel column to obtain 445 mg of white solid with a yield of 92%.
实施例15.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦Example 15. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -diisopropylphosphine
Figure PCTCN2019088461-appb-000028
Figure PCTCN2019088461-appb-000028
在惰性气体保护下中量取二异丙基膦(1.48mL,10.0mmol)加入到50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,搅拌反应2小时,制得二异丙基膦锂溶液.另取一个50mL的史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖滴加入二异丙基膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,分离出有机相,用无水Nɑ 2SO 4干燥,减压抽除溶剂.混合物用甲醇重结晶,得到3.6g白色固体,产率94％。 Under the protection of inert gas, diisopropylphosphine (1.48mL, 10.0mmol) was added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane solution, 10.5) was added dropwise at -78 ° C mmol), after about 5 minutes of dripping, return to room temperature, stir the reaction for 2 hours to prepare a lithium diisopropylphosphonate solution. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6 -Oxy-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add lithium diisopropylphosphonate solution through a double needle tip, and stir to react 6 hours. Add 0.5 mL of methanol under ice water bath, remove the solvent under reduced pressure, add 15 mL of dichloromethane to dissolve the residue, and then wash the solution with saturated ammonium chloride, separate the organic phase, and dry with anhydrous Nɑ 2 SO 4 , The solvent was removed under reduced pressure. The mixture was recrystallized from methanol to obtain 3.6 g of white solid with a yield of 94%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-1.18。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-1.18.
实施例16.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦-硼烷Example 16. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -diisopropylphosphine-borane
Figure PCTCN2019088461-appb-000029
Figure PCTCN2019088461-appb-000029
在惰性气体保护下称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦(3.8g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后搅拌3小时.减压抽去溶剂,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,经过一根短硅胶柱提纯,得到3.9g白色泡沫状固体,产率98％。mp:62.3～65.7℃。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyranoglycosyl-3) -diisopropylphosphine (3.8g, 10mmol) under inert gas protection , Add borane in tetrahydrofuran solution (1.0M, 11mL, 11mmol) dropwise at -20 ℃, return to room temperature and stir for 3 hours. Remove the solvent under reduced pressure, add 0.5mL of methanol to the residue, and then add 15mL of dichloromethane Methane was dissolved and purified through a short silica gel column to obtain 3.9 g of white foamy solid with a yield of 98%. mp: 62.3 ～ 65.7 ℃.
1H NMR(400MHz,CDCl 3)δ7.42(ddd,J＝23.6,7.3,3.2Hz,5H),5.61(s,1H),4.80–4.27(m,4H),3.98(td,J＝9.9,5.0Hz,1H),3.78(t,J＝10.2Hz,1H),3.62–3.30(m,4H),3.03–2.75(m,2H),2.54(tt,J＝14.1,6.9Hz,1H),1.32(ddd,J＝24.3,14.8,7.3Hz,6H),1.25–1.11(m,6H),0.50(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (ddd, J = 23.6, 7.3, 3.2 Hz, 5H), 5.61 (s, 1H), 4.80–4.27 (m, 4H), 3.98 (td, J = 9.9 , 5.0Hz, 1H), 3.78 (t, J = 10.2Hz, 1H), 3.62–3.30 (m, 4H), 3.03–2.75 (m, 2H), 2.54 (tt, J = 14.1, 6.9Hz, 1H) , 1.32 (ddd, J = 24.3, 14.8, 7.3 Hz, 6H), 1.25-1.11 (m, 6H), 0.50 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.24(s),129.04(s),128.32(s),125.92(s),102.60(s),100.87(s),77.34(d,J＝32.0Hz),69.82(s),68.82(d,J＝6.1Hz),60.86(s),54.87(s),38.64(s),38.43(s),21.67(d,J＝15.5Hz),21.37(d,J＝20.2Hz),20.30(d,J＝2.2Hz),18.70(s),18.01(s)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.24 (s), 129.04 (s), 128.32 (s), 125.92 (s), 102.60 (s), 100.87 (s), 77.34 (d, J = 32.0Hz) , 69.82 (s), 68.82 (d, J = 6.1Hz), 60.86 (s), 54.87 (s), 38.64 (s), 38.43 (s), 21.67 (d, J = 15.5Hz), 21.37 (d, J = 20.2 Hz), 20.30 (d, J = 2.2 Hz), 18.70 (s), 18.01 (s).
31P{ 1H}NMR(162MHz,CDCl 3)δ39.81。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 39.81.
HRMS(ESI)理论值C 20H 34BO 5P+H +:397.2313.实测值:397.2278。 HRMS (ESI) theoretical value C 20 H 34 BO 5 P + H + : 397.2313. Found: 397.2278.
实施例17.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦-硼烷Example 17. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -diisopropylphosphine-boron alkyl
Figure PCTCN2019088461-appb-000030
Figure PCTCN2019088461-appb-000030
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷(3.96g,10.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴冷却,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(1.3mL,20.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到4.1g白色固体,产率99％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine-borane (3.96g, 10.0mmol) in In a 50mL Shrek bottle, pump and ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool in an ice water bath, add NɑH (60% kerosene mixture, 400mg) under an inert gas atmosphere, stir for 1 hour, and cool with ice / sodium chloride system To -10 ℃, add methyl iodide (1.3mL, 20.0mmol) dropwise, and stir the reaction for 6 hours. The solvent was removed under reduced pressure, the residue was dissolved with 20mL of dichloromethane, then filtered through celite, and purified by silica gel column chromatography To obtain 4.1 g of white solid with a yield of 99%.
1H NMR(400MHz,CDCl 3)δ7.45–7.33(m,5H),5.57(s,1H),4.65(s,1H),4.37(ddd,J＝20.3,10.2,7.2Hz,2H),4.31(dd,J＝10.6,5.1Hz,1H),4.13(d,J＝6.5Hz,1H),3.93(td,J＝10.2,5.1Hz,1H),3.74(t,J＝10.2Hz,1H),3.46(s,3H),3.40(s,3H),2.93(dhept,J＝21.0,7.0Hz,1H),2.84(dd,J＝12.2,7.3Hz,1H),2.59(dhept,J＝21.0,7.0Hz,1H),1.38(dd,J＝12.5,7.4Hz,3H),1.29(dd,J＝17.1,7.4Hz,3H),1.17(ddd,J＝15.7,10.6,7.0Hz,6H),0.43(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.45–7.33 (m, 5H), 5.57 (s, 1H), 4.65 (s, 1H), 4.37 (ddd, J = 20.3, 10.2, 7.2 Hz, 2H), 4.31 (dd, J = 10.6, 5.1 Hz, 1H), 4.13 (d, J = 6.5 Hz, 1H), 3.93 (td, J = 10.2, 5.1 Hz, 1H), 3.74 (t, J = 10.2 Hz, 1H) ), 3.46 (s, 3H), 3.40 (s, 3H), 2.93 (dhept, J = 21.0, 7.0 Hz, 1H), 2.84 (dd, J = 12.2, 7.3 Hz, 1H), 2.59 (dhept, J = 21.0, 7.0Hz, 1H), 1.38 (dd, J = 12.5, 7.4Hz, 3H), 1.29 (dd, J = 17.1, 7.4Hz, 3H), 1.17 (ddd, J = 15.7, 10.6, 7.0Hz, 6H ), 0.43 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.28(s),129.00(s),128.33(s),125.83(s),102.60(s),98.84(s),77.96(d,J＝6.9Hz),77.41(d,J＝8.0Hz),69.83(s),60.42(s),57.65 (s),54.75(s),35.13(s),34.92(s),21.31(dd,J＝29.9,10.9Hz),20.37(d,J＝3.0Hz),18.77(d,J＝1.9Hz),18.08–17.75(m)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.28 (s), 129.00 (s), 128.33 (s), 125.83 (s), 102.60 (s), 98.84 (s), 77.96 (d, J = 6.9Hz) , 77.41 (d, J = 8.0 Hz), 69.83 (s), 60.42 (s), 57.65 (s), 54.75 (s), 35.13 (s), 34.92 (s), 21.31 (dd, J = 29.9, 10.9 Hz), 20.37 (d, J = 3.0 Hz), 18.77 (d, J = 1.9 Hz), 18.08-17.75 (m).
31P{ 1H}NMR(162MHz,CDCl 3)δ40.95。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 40.95.
HRMS(ESI)理论值C 21H 36BO 5P+Na +:433.2289.实测值:433.2313。 HRMS (ESI) theoretical value C 21 H 36 BO 5 P + Na + : 433.2289. Found: 433.2313.
实施例18.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦Example 18. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -diisopropylphosphine
Figure PCTCN2019088461-appb-000031
Figure PCTCN2019088461-appb-000031
实施例18-1.Example 18-1.
称取(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦-硼烷(4.1g,10.0mmol)置于史莱克瓶中,抽换气三次,注入5mL已脱氧乙醇,油浴80℃加热搅拌3小时,回至室温.减压抽除溶剂,剩余油状物过一根短的硅胶柱,得到3.9g白色固体,产率99％。Weigh out (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -diisopropylphosphine-borane ( 4.1g, 10.0mmol) placed in a Shrek bottle, pumping and ventilating three times, injecting 5mL of deoxygenated ethanol, heating and stirring in an oil bath at 80 ℃ for 3 hours, and returning to room temperature. The solvent was removed under reduced pressure, and the remaining oil was too short The silica gel column yielded 3.9g of white solid with a yield of 99%.
实施例18-2.Example 18-2.
称取(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二异丙基膦-硼烷(4.1g,10.0mmol)置于史莱克瓶中,抽换气三次,注入0.5mL已脱氧的二乙胺和5mL的乙醇中,油浴80℃加热搅拌3小时,回至室温.减压抽除过量的二乙胺,剩余油状物过一根短的硅胶柱,抽去溶剂,得到3.9g白色固体,产率99％。Weigh out (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -diisopropylphosphine-borane ( 4.1g, 10.0mmol) placed in a Shrek bottle, pumped and ventilated three times, poured into 0.5mL of deoxygenated diethylamine and 5mL of ethanol, heated and stirred in an oil bath at 80 ℃ for 3 hours, and returned to room temperature. Excess diethylamine and the remaining oil were passed through a short silica gel column and the solvent was removed to obtain 3.9g of white solid with a yield of 99%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-0.81。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-0.81.
实施例19.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-双(邻甲基苯基)膦Example 19. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -bis (o-methylphenyl) phosphine
Figure PCTCN2019088461-appb-000032
Figure PCTCN2019088461-appb-000032
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气. 量取2-溴甲苯(1.7g,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加的四氢呋喃溶液,控制滴加速度使反应液保持微沸状态.滴加完毕后,65℃回流两小时.于惰性气体保护下中量取三氯化磷(0.67g,10.0mmol),和10mL的无水四氢呋喃置于另一100mL史莱克瓶中,于-78℃下,将2-溴甲苯格氏试剂通过双针尖滴加至三氯化磷溶液中,滴加完毕后,待其回到室温,搅拌反应2小时.另取一100mL史莱克瓶,加入四氢锂铝(370mg,10.0mmol),注入10mL的无水乙醚,用冰水冷至0℃,将二(邻甲基苯基)氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5.0g的十水硫酸钠搅拌除去残余的四氢锂铝,溶液在氮气下通过硅藻土过滤,再加入无水硫酸钠干燥后,转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(2.19mL,2.4M的正己烷溶液,5.3mmol),约5分钟滴完,回至室温,搅拌反应2小时.另取一100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(1.2g,4.5mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入双(2-甲基苯基)膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1.0M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,用无水Na 2SO 4干燥,减压抽除溶剂,乙醇重结晶,得到1.8g白色粉末,产率83％。mp:130.1～133.3℃。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the magnesium scraps with a heated air gun for 15 minutes. After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Measure 2-bromotoluene (1.7g, 10.0mmol) and 10mL of anhydrous tetrahydrofuran into a constant pressure funnel , Add 0.5mL into the three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the tetrahydrofuran solution to the three-necked bottle to control the dripping rate to keep the reaction solution slightly boiling. 65 Reflux at ℃ for two hours. Under the protection of inert gas, weigh phosphorus trichloride (0.67g, 10.0mmol), and 10mL of anhydrous tetrahydrofuran in another 100mL Shrek bottle, at -78 ℃, the 2- Bromotoluene Grignard reagent was added dropwise to the phosphorus trichloride solution through a double needle tip. After the addition was completed, wait for it to return to room temperature and stir for 2 hours. Take another 100mL Shrek bottle and add lithium aluminum hydride (370mg, 10.0mmol), inject 10mL of anhydrous ether, cool to 0 ° C with ice water, and add the bis (o-methylphenyl) phosphine chloride solution dropwise to the lithium tetrahydrogen aluminum solution through the double needle tip Stir the reaction for 2 hours. Stir with 5.0g of sodium sulfate decahydrate to remove the residual lithium aluminum hydride. The solution is filtered through diatomaceous earth under nitrogen. After adding anhydrous sodium sulfate to dry, it is transferred to another pump. A 100mL Shrek bottle with three gas injections. Cool to -78 ° C, add n-butyllithium (2.19mL, 2.4M n-hexane solution, 5.3mmol) dropwise, drop to the end after about 5 minutes, return to room temperature, and stir the reaction 2 hours. Take another 100mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (1.2g, 4.5mmol) Three times, inject 10mL of tetrahydrofuran to stir and dissolve, add bis (2-methylphenyl) phosphine lithium solution through a double needle tip, and stir to react for 6 hours. Add 0.5mL of methanol under ice water bath, stir for half an hour, remove the solvent under reduced pressure, add Dissolve the residue in 15 mL of dichloromethane, then wash the solution to neutrality with hydrochloric acid (1.0 M, 15 mL), then wash the organic phase three times with saturated brine (20 mL), dry over anhydrous Na 2 SO 4 , and remove under reduced pressure The solvent and ethanol were recrystallized to obtain 1.8 g of white powder with a yield of 83%. mp: 130.1 ～ 133.3 ℃.
Figure PCTCN2019088461-appb-000033
(c 1.3,CH 2Cl 2)。
Figure PCTCN2019088461-appb-000033
(c 1.3, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝3.3Hz,1H),7.35(d,J＝5.5Hz,1H),7.22–6.96(m,9H),6.80(d,J＝7.5Hz,2H),5.52(s,1H),4.61(m,1H),4.54–4.41(m,1H),4.45(s,1H),4.29(dd,J＝10.2,4.7Hz,1H),3.81(t,J＝10.2Hz,1H),3.59(d,J＝3.3Hz,1H),3.46(dd,J＝3.3Hz,1H),3.41(s,3H),2.73(s,3H),2.32(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 3.3 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 7.22–6.96 (m, 9H), 6.80 (d, J = 7.5Hz, 2H), 5.52 (s, 1H), 4.61 (m, 1H), 4.54-4.41 (m, 1H), 4.45 (s, 1H), 4.29 (dd, J = 10.2, 4.7Hz, 1H), 3.81 (t, J = 10.2 Hz, 1H), 3.59 (d, J = 3.3 Hz, 1H), 3.46 (dd, J = 3.3 Hz, 1H), 3.41 (s, 3H), 2.73 (s, 3H), 2.32 (s, 3H).
13C NMR(101MHz,CDCl 3)δ144.75(s),144.45(s),141.90(s),141.61(s),138.71(d,J＝17.9Hz),137.16(s),135.27(s),134.02(s),130.30(s),129.92(dd,J＝20.9,5.5Hz),128.71(s),128.26(s),127.68(s),127.42(s),125.96(d,J＝18.0Hz),125.09(s),101.14(s),100.89(s),77.10(d,J＝10.5Hz),70.16(s),69.23(s),60.59(d,J＝12.0Hz),54.74(s),40.83(s),40.58(s),21.34(dd,J＝23.6,8.4Hz)。 13 C NMR (101 MHz, CDCl 3 ) δ 144.75 (s), 144.45 (s), 141.90 (s), 141.61 (s), 138.71 (d, J = 17.9 Hz), 137.16 (s), 135.27 (s) , 134.02 (s), 130.30 (s), 129.92 (dd, J = 20.9, 5.5Hz), 128.71 (s), 128.26 (s), 127.68 (s), 127.42 (s), 125.96 (d, J = 18.0 Hz), 125.09 (s), 101.14 (s), 100.89 (s), 77.10 (d, J = 10.5Hz), 70.16 (s), 69.23 (s), 60.59 (d, J = 12.0Hz), 54.74 ( s), 40.83 (s), 40.58 (s), 21.34 (dd, J = 23.6, 8.4 Hz).
31P{ 1H}NMR(162MHz,CDCl 3)δ-48.41. 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-48.41.
HRMS(ESI)理论值C 28H 31O 5P+H +:479.1981.实测值:479.1973。 HRMS (ESI) theoretical value C 28 H 31 O 5 P + H + : 479.1981. Found value: 479.1973.
实施例20.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-双(2-联苯基)膦Example 20. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -bis (2-biphenyl) phosphine
Figure PCTCN2019088461-appb-000034
Figure PCTCN2019088461-appb-000034
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,注入2-溴联苯(2.3g,10mmol),于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,搅拌反应1小时.于-78℃下,加入三氯化磷(0.68g,5mmol),缓慢回到-40℃再搅拌反应1小时.剪入金属锂(200mg),搅拌反应24小时.另取一个100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.9g,9.0mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入上面制备的双(2-联苯基)膦锂溶液,搅拌反应6小时.加入0.5mL甲醇淬灭反应,减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,混合物用硅胶柱层析分离,得到2.4g白色固体,产率79％。Place a 50mL three-necked flask, a spherical condenser, and a constant pressure funnel in a 150 ° C oven to dry overnight and assemble while hot. After pumping and ventilating three times, inject 2-bromobiphenyl (2.3g, 10mmol) at -78 ° C. N-Butyllithium (4.4mL, 2.4M n-hexane solution, 10.5mmol) was added dropwise, about 5 minutes after the completion of the drop, the reaction was stirred for 1 hour. At -78 ℃, phosphorus trichloride (0.68g, 5mmol) was added, Slowly return to -40 ° C and stir for another hour. Cut in lithium metal (200mg) and stir for 24 hours. Take another 100mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzene Methylene-ɑ-D-mannopyranoside (2.9g, 9.0mmol), ventilate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add the bis (2-biphenyl) phosphine prepared above through a double needle tip at room temperature Lithium solution, stirring reaction for 6 hours. The reaction was quenched by adding 0.5 mL of methanol, the solvent was removed under reduced pressure, the residue was dissolved with 20 mL of dichloromethane, then filtered through celite, and purified by silica gel column chromatography, and the mixture was purified by silica gel column layer After analysis, 2.4 g of white solid was obtained with a yield of 79%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-46.37。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-46.37.
实施例21.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-双(2-联苯基)膦Example 21. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -bis (2-biphenyl )phosphine
Figure PCTCN2019088461-appb-000035
Figure PCTCN2019088461-appb-000035
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-双(2-联苯基)膦(1.2g,5.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.13mL,5.0 mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.1g白色固体,产率71％。mp:168.5～169.6℃。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -bis (2-biphenyl) phosphine (1.2g, 5.0mmol) Place in a 50mL Shrek bottle, pump and ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NɑH (60% kerosene mixture, 400mg) under an inert gas atmosphere, stir for 1 hour, use The ice / sodium chloride system was cooled to -10 ° C, iodomethane (0.13 mL, 5.0 mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20 mL of dichloromethane, and then filtered through celite Separated and purified by silica gel column chromatography to obtain 1.1g white solid with a yield of 71%. mp: 168.5 ～ 169.6 ℃.
1H NMR(400MHz,CDCl 3)δ7.96(d,J＝84.7Hz,2H),7.34(dd,J＝13.9,7.3Hz,4H),7.25–6.98(m,13H),6.91(d,J＝7.4Hz,2H),6.68(d,J＝7.7Hz,2H),5.46(s,1H),4.44(s,1H),4.40–4.30(m,1H),4.25–4.14(m,2H),3.74(dd,J＝19.7,7.8Hz,2H),3.31(s,3H),3.02–2.82(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 84.7 Hz, 2H), 7.34 (dd, J = 13.9, 7.3 Hz, 4H), 7.25-6.98 (m, 13H), 6.91 (d, J = 7.4Hz, 2H), 6.68 (d, J = 7.7Hz, 2H), 5.46 (s, 1H), 4.44 (s, 1H), 4.40-4.30 (m, 1H), 4.25-4.14 (m, 2H ), 3.74 (dd, J = 19.7, 7.8 Hz, 2H), 3.31 (s, 3H), 3.02-2.82 (m, 4H).
13C NMR(101MHz,CDCl 3)δ149.25(d,J＝30.0Hz),148.28(d,J＝33.7Hz),142.44(d,J＝6.2Hz),141.89(d,J＝4.5Hz),137.83(d,J＝25.4Hz),137.31(s),135.25(d,J＝27.7Hz),131.82(s),131.29(d,J＝5.5Hz),130.74(d,J＝5.3Hz),130.54(d,J＝4.4Hz),130.45(d,J＝5.4Hz),128.73(s),128.08(s),127.63(d,J＝3.9Hz),127.37(s),127.15(s),126.94(s),126.59(s),126.39(s),126.20(s),125.63(s),101.01(s),98.28(s),79.13(d,J＝9.2Hz),77.62(d,J＝10.9Hz),69.35(s),60.26(d,J＝11.9Hz),57.59(s),53.67(s),39.62(d,J＝30.9Hz)。 13 C NMR (101 MHz, CDCl 3 ) δ 149.25 (d, J = 30.0 Hz), 148.28 (d, J = 33.7 Hz), 142.44 (d, J = 6.2 Hz), 141.89 (d, J = 4.5 Hz) , 137.83 (d, J = 25.4 Hz), 137.31 (s), 135.25 (d, J = 27.7 Hz), 131.82 (s), 131.29 (d, J = 5.5 Hz), 130.74 (d, J = 5.3 Hz) , 130.54 (d, J = 4.4 Hz), 130.45 (d, J = 5.4 Hz), 128.73 (s), 128.08 (s), 127.63 (d, J = 3.9 Hz), 127.37 (s), 127.15 (s) , 126.94 (s), 126.59 (s), 126.39 (s), 126.20 (s), 125.63 (s), 101.01 (s), 98.28 (s), 79.13 (d, J = 9.2Hz), 77.62 (d, J = 10.9 Hz), 69.35 (s), 60.26 (d, J = 11.9 Hz), 57.59 (s), 53.67 (s), 39.62 (d, J = 30.9 Hz).
31P{ 1H}NMR(162MHz,CDCl 3)δ-52.12。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-52.12.
HRMS(ESI)理论值C 39H 37O 5P+H +:617.2451.实测值:617.2447。 HRMS (ESI) theoretical value C 39 H 37 O 5 P + H + : 617.2451. Found: 617.2447.
实施例22.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基环己基膦-硼烷 Example 22. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3) -tert-butylcyclohexyl Phosphine-borane
Figure PCTCN2019088461-appb-000036
Figure PCTCN2019088461-appb-000036
50mL三口瓶,球形冷凝管,恒压漏斗,于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol),抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取氯代环己烷(1.2mL,10.0mmol)和10mL无水四氢呋喃于恒压漏斗中,通过恒压漏斗先滴加0.5mL溶液进入三口瓶中,搅拌至反应引发后,再往三口瓶中滴加氯代环己烷的四氢呋喃溶液,控制滴加速度使反应液保持微沸状态.滴加完毕后,65℃回流两小时制得环己基氯化镁格氏试剂.另取一100mL史莱克瓶,于惰性气体保护下中量取二氯叔丁基膦(2.1mL,10.0mmol)和10mL的无水四氢呋喃,于-40℃ 下,将环己基氯化镁格氏试剂通过双针尖滴加至二氯叔丁基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时制得叔丁基环己基氯化膦.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将环己基叔丁基氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液在氮气下通过硅藻土过滤,再加入无水硫酸钠干燥,转移至另一已抽换气三次的100mL的史莱克瓶,冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时制得叔丁基环己基膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖将加入叔丁基环己基膦锂溶液,搅拌反应6小时.于-20℃下滴加硼烷的四氢呋喃溶液(15mL,1M,15mmol),回至室温后搅拌3小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Nɑ 2SO 4干燥,减压抽除溶剂.产物用硅胶柱层析提纯,得到3.5g白色泡沫状固体,产率78％。mp:147.2～150.3℃。 50mL three-necked bottle, spherical condenser, constant pressure funnel, dried in an oven at 150 ℃ overnight, assembled while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) and pump to a vacuum state. Heat the activated magnesium scraps with a heated air gun for 15 minutes, and after the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure chlorocyclohexane (1.2mL, 10.0mmol) and 10mL of anhydrous tetrahydrofuran in a constant pressure funnel, Add 0.5mL of solution into the three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the tetrahydrofuran solution of chlorocyclohexane to the three-necked bottle to control the dripping rate to keep the reaction solution slightly boiling. After completion, reflux at 65 ° C for two hours to prepare the Grignard reagent of cyclohexylmagnesium chloride. Take another 100mL Shrek bottle and measure dichloro-tert-butylphosphine (2.1mL, 10.0mmol) and 10mL Water tetrahydrofuran, at -40 ℃, cyclohexylmagnesium chloride Grignard reagent was added dropwise to the dichloro-tert-butylphosphine solution through a double needle tip, after the completion of the dropwise addition, wait for it to return to room temperature, stir the reaction for 2 hours to prepare a tert-butyl ring Hexylphosphine chloride. Take another 100mL Shrek bottle, weigh it into lithium aluminum hydride (370mg, 10.0mmol), and inject 10mL of anhydrous Hydrogen furan, cooled to 0 ° C with ice water, the cyclohexyl tert-butylphosphine chloride solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours. 5g of sodium sulfate decahydrate was used to remove residual tetrahydrogen Lithium aluminum, the solution was filtered through diatomaceous earth under nitrogen, then dried over anhydrous sodium sulfate, transferred to another 100mL Shrek bottle that had been ventilated three times, cooled to -78 ° C, and n-butyl was added dropwise to it Lithium (4.38mL, 2.4M n-hexane solution, 10.5mmol), after 5 minutes of dripping, return to room temperature, stir the reaction for 2 hours to prepare a lithium tert-butylcyclohexylphosphine solution. Take another 50mL Shrek bottle and weigh into the methyl group 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran and stirring to dissolve, add the uncle through the double needle tip Lithium butylcyclohexylphosphine solution, stirring and reacting for 6 hours. A solution of borane in tetrahydrofuran (15mL, 1M, 15mmol) was added dropwise at -20 ° C, returning to room temperature and stirring for 3 hours. The reaction solution was added with 0.5mL of methanol in an ice water bath. After stirring for half an hour, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and then the solution was washed with hydrochloric acid (1M, 15 mL) to neutrality, followed by washing with saturated brine (20 mL). Three times, dried over anhydrous Nɑ 2 SO 4, solvent extraction under reduced pressure. The product was purified by silica gel column chromatography, to give a white foamy solid 3.5g, 78% yield. mp: 147.2 ～ 150.3 ℃.
1H NMR(400MHz,CDCl 3)δ7.52–7.19(m,5H),5.49(d,J＝23.7Hz,1H),4.59(dd,J＝27.9,4.0Hz,1H),4.42–4.14(m,3H),4.04–3.88(m,1H),3.66(t,J＝9.7Hz,1H),3.49–3.29(m,3H),3.01–2.59(m,1H),2.42(ddd,J＝36.9,25.5,13.4Hz,1H),2.07–1.38(m,9H),1.38–0.09(m,19H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.52-7.19 (m, 5H), 5.49 (d, J = 23.7 Hz, 1H), 4.59 (dd, J = 27.9, 4.0 Hz, 1H), 4.42-4.14 ( m, 3H), 4.04–3.88 (m, 1H), 3.66 (t, J = 9.7 Hz, 1H), 3.49–3.29 (m, 3H), 3.01–2.59 (m, 1H), 2.42 (ddd, J = 36.9, 25.5, 13.4 Hz, 1H), 2.07–1.38 (m, 9H), 1.38–0.09 (m, 19H).
31P{ 1H}NMR(162MHz,CDCl 3)δ44.86,41.01。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ 44.86, 41.01.
实施例23.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-(2-甲氧苯基)-苯基膦 Example 23. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3)-(2- Methoxyphenyl) -phenylphosphine
Figure PCTCN2019088461-appb-000037
Figure PCTCN2019088461-appb-000037
50mL三口瓶,球形冷凝管,恒压漏斗,于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态, 用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取邻溴苯甲醚(1.25mL,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,先把恒压漏斗中的溶液滴加0.5mL溶液进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加2-溴苯甲醚的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回流两小时.另取一100mL的史莱克瓶,于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol)溶于10mL的无水四氢呋喃.于-40℃下,将2-苯甲醚溴化镁格氏试剂通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时制得苯基-2-甲氧基苯基氯化膦溶液。另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,反应液用冰水冷至0℃,将苯基-2-甲氧基苯基氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.加入5g的十水硫酸钠，搅拌反应除去残余的四氢锂铝,溶液再氮气下通过硅藻土过滤到含有无水硫酸钠反应瓶中干燥,再转移至另一已抽换气三次的50mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时制得苯基-2-甲氧基苯基膦锂溶液.另取一100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖滴加苯基-(2-甲氧基苯基)膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Nɑ 2SO 4干燥,减压抽除溶剂.产物用硅胶柱层析分离提纯,得到3.3g白色泡沫状固体,产率68％。mp:181.4～185.4℃。 50mL three-necked bottle, spherical condenser, constant pressure funnel, dried in a 150 ° C oven overnight, assembled while hot. After pumping and ventilating three times, weigh into the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. To a vacuum state, heat the activated magnesium scraps with a heated air gun for 15 minutes, and after the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure o-bromoanisole (1.25mL, 10.0mmol) and 10mL of anhydrous tetrahydrofuran into Heng In the pressure funnel, first add 0.5mL of the solution in the constant pressure funnel to the three-necked bottle, stir until the reaction is initiated, and then add the tetrahydrofuran solution of 2-bromoanisole to the three-necked bottle to control the dripping rate so that the reaction solution Maintain slightly boiling state. After the dropwise addition, reflux at 65 ° C for two hours. Take another 100mL Shrek bottle and measure dichlorophenylphosphine (1.35mL, 10.0mmol) in 10mL without the protection of inert gas. Water tetrahydrofuran. At -40 ° C, add 2-anisole magnesium bromide Grignard reagent to the dichlorophenylphosphine solution through a double needle tip. After the addition is complete, wait for it to return to room temperature and stir for 2 hours. A phenyl-2-methoxyphenylphosphine chloride solution was prepared. Take another 100mL Shrek bottle, weigh it into lithium tetrahydrogen aluminum (370mg, 10.0mmol), inject 10mL of anhydrous tetrahydrofuran, the reaction solution is cooled to 0 ° C with ice water, and phenyl-2-methoxyphenyl is chlorinated The phosphine solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours. 5 g of sodium sulfate decahydrate was added, and the reaction was stirred to remove the residual lithium aluminum tetrahydride. The solution was filtered through celite under nitrogen to contain no Sodium sulfate in water reaction bottle was dried, and then transferred to another 50mL Shrek bottle that has been pumped and ventilated three times. Cooled to -78 ℃, to which n-butyllithium (4.38mL, 2.4M n-hexane solution was added dropwise) 10.5mmol), after 5 minutes of dripping, return to room temperature, stir the reaction for 2 hours to prepare a phenyl-2-methoxyphenylphosphine lithium solution. Take another 100mL Shrek bottle and weigh into methyl 2,3-anhydride -4,6-Oxy-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, add phenyl- (2- Lithium methoxyphenyl) phosphine solution, stirring and reacting for 6 hours. The reaction solution was added with 0.5mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15mL of dichloromethane was added to dissolve the residue, and then hydrochloric acid (1M , 15mL) The solution was washed to Resistance, followed by saturated brine (20mL) The organic phase was washed three times, dried over anhydrous Nɑ 2 SO 4, solvent extraction under reduced pressure. The product was purified by silica gel column chromatography, to give a white foamy solid 3.3g, 68% yield . mp: 181.4 ～ 185.4 ℃.
31P{ 1H}NMR(162MHz,CDCl 3)δ-12.70,-13.07。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-12.70, -13.07.
实施例24.(R p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-(2-二甲基氨基苯基)-苯基膦 Example 24. (R p )-(Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azarapyranoside-3)-(2-dimethylaminophenyl ) -Phenylphosphine
Figure PCTCN2019088461-appb-000038
Figure PCTCN2019088461-appb-000038
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热 组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取2-溴-N,N-二甲基苯胺(1.44mL,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回流两小时.于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol)溶于10mL的无水四氢呋喃中.于-78℃下,将2-N,N-二甲基苯胺溴化镁溶液通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将苯基-(2-二甲基氨基苯基)氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.加入5g的十水硫酸钠搅拌除去残余的四氢锂铝,溶液再氮气下通过硅藻土过滤到带有无水硫酸钠反应瓶中干燥,再转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时制得苯基-(2-二甲氨基苯基)膦锂.另取一100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入苯基-(2-二甲基氨基苯基)膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Nɑ 2SO 4干燥,减压抽除溶剂.产物用硅胶柱层析分离提纯,得到3.1g灰白色泡沫状固体,产率63％。mp:158.5～159.9℃。
Figure PCTCN2019088461-appb-000039
(c 1.8,CH 2Cl 2)。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the magnesium scraps with a heated air gun for 15 minutes. After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure 2-bromo-N, N-dimethylaniline (1.44mL, 10.0mmol ) And 10mL of anhydrous tetrahydrofuran into a constant pressure funnel, through the constant pressure funnel, first drop 0.5mL into a three-necked bottle, stir until the reaction is initiated, and then add the tetrahydrofuran solution dropwise to the three-necked bottle, control the drop acceleration to keep the reaction solution Slightly boiling state. After the dropwise addition, reflux at 65 ° C for two hours. Take dichlorophenylphosphine (1.35mL, 10.0mmol) in 10mL of anhydrous tetrahydrofuran under the protection of inert gas. At -78 ° C, Add 2-N, N-dimethylaniline magnesium bromide solution to the dichlorophenylphosphine solution dropwise through a double needle tip.After the dropwise addition, wait for it to return to room temperature and stir for 2 hours. Take another 100mL In a black bottle, weigh lithium aluminum tetrahydrogen (370mg, 10.0mmol), inject 10mL of anhydrous tetrahydrofuran, cool to 0 ° C with ice water, and dissolve phenyl- (2-dimethylaminophenyl) phosphine chloride It was added dropwise to the lithium aluminum tetrahydrogen solution through a double needle tip, and the reaction was stirred for 2 hours. 5 g of sodium sulfate decahydrate was added to stir to remove the residual lithium aluminum tetrahydride, and the solution was filtered through celite under nitrogen to anhydrous sodium sulfate. The reaction bottle was dried, and then transferred to another 100 mL Shrek bottle that had been ventilated three times. Cooled to -78 ° C, and n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.5mmol) was added dropwise to it After 5 minutes of dripping, return to room temperature and stir the reaction for 2 hours to prepare phenyl- (2-dimethylaminophenyl) phosphine lithium. Take another 100mL Shrek bottle and weigh in methyl 2,3-anhydride-4 , 6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add phenyl- (2-dimethyl Lithium aminophenyl) phosphine solution, stirring and reacting for 6 hours. The reaction solution was added with 0.5mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15mL of methylene chloride was added to dissolve the residue, and then hydrochloric acid (1M, 15mL ) solution was washed to neutral, then with saturated brine (20mL) the organic phase was washed three times, dried over anhydrous Nɑ 2 SO 4, solvent was removed under reduced pressure suction. the product was isolated by silica gel column chromatography to give an off-white foam 3.1g In a yield of 63%. mp: 158.5 ～ 159.9 ℃.
Figure PCTCN2019088461-appb-000039
(c 1.8, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.81(d,J＝6.3Hz,1H),7.48(d,J＝3.0Hz,2H),7.33–7.26(m,1H),7.22(d,J＝1.0Hz,3H),7.18–7.08(m,3H),7.05(t,J＝5.8Hz,2H),6.84(d,J＝6.3Hz,2H),5.52(s,1H),4.66(d,J＝1.6Hz,1H),4.47(d,J＝15.0Hz,2H),4.33–4.21(m,1H),3.86–3.73(m,1H),3.51–3.31(m,5H),2.34(d,J＝10.2Hz,6H),1.99(s,1H),1.63(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 6.3 Hz, 1H), 7.48 (d, J = 3.0 Hz, 2H), 7.33–7.26 (m, 1H), 7.22 (d, J = 1.0Hz, 3H), 7.18-7.08 (m, 3H), 7.05 (t, J = 5.8Hz, 2H), 6.84 (d, J = 6.3Hz, 2H), 5.52 (s, 1H), 4.66 (d, J = 1.6 Hz, 1H), 4.47 (d, J = 15.0 Hz, 2H), 4.33–4.21 (m, 1H), 3.86–3.73 (m, 1H), 3.51–3.31 (m, 5H), 2.34 (d , J = 10.2 Hz, 6H), 1.99 (s, 1H), 1.63 (s, 1H).
13C NMR(101MHz,CDCl 3)δ157.58(d,J＝19.9Hz),139.18(d,J＝17.3Hz),137.39(d,J＝9.3Hz),134.91(d,J＝21.2Hz),131.81(s),128.81(s),128.15(d,J＝14.5Hz),127.68(d,J＝6.1Hz),125.90(s),124.02(s),121.21(s),101.44(s),101.01 (s),77.25(d,J＝10.9Hz),70.15(d,J＝6.6Hz),69.26(s),60.58(d,J＝12.8Hz),54.98(s),45.43(s),41.23(d,J＝28.6Hz)。 13 C NMR (101 MHz, CDCl 3 ) δ 157.58 (d, J = 19.9 Hz), 139.18 (d, J = 17.3 Hz), 137.39 (d, J = 9.3 Hz), 134.91 (d, J = 21.2 Hz) , 131.81 (s), 128.81 (s), 128.15 (d, J = 14.5Hz), 127.68 (d, J = 6.1Hz), 125.90 (s), 124.02 (s), 121.21 (s), 101.44 (s) , 101.01 (s), 77.25 (d, J = 10.9 Hz), 70.15 (d, J = 6.6 Hz), 69.26 (s), 60.58 (d, J = 12.8 Hz), 54.98 (s), 45.43 (s) , 41.23 (d, J = 28.6 Hz).
31P{ 1H}NMR(162MHz,CDCl 3)δ-33.05。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-33.05.
实施例25.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-(2-噻吩基)-苯基膦 Example 25. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3)-(2- Thienyl) -phenylphosphine
Figure PCTCN2019088461-appb-000040
Figure PCTCN2019088461-appb-000040
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取2-溴噻吩(0.97mL,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回流两小时制得2-噻吩基溴化镁.另取一100mL史莱克瓶于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol)溶于10mL的无水四氢呋喃中.于-78℃下,将2-噻吩溴化镁格氏试剂通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时制得苯基-(2-噻吩基)氯化膦溶液.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将苯基-(2-噻吩基)氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.加入5g的十水硫酸钠搅拌除去残余的四氢锂铝,溶液通过硅藻土过滤,加入无水硫酸钠干燥后,再转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时制得苯基-(2-噻吩基)膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖滴入苯基-(2-噻吩基)膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15 mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,用无水Nɑ 2SO 4干燥,减压抽除溶剂,用硅胶柱层析分离提纯,得到3.7g淡红色泡沫状固体,产率81％。mp:70.2～73.0℃。
Figure PCTCN2019088461-appb-000041
(c 3.5,CH 2Cl 2)。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the activated magnesium scraps with a heated air gun for 15 minutes. After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure 2-bromothiophene (0.97mL, 10.0mmol) and 10mL of anhydrous tetrahydrofuran into the constant Pressure funnel, add 0.5mL into a three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add a tetrahydrofuran solution to the three-necked bottle, control the dripping rate to keep the reaction solution slightly boiling. , Reflux at 65 ℃ for two hours to prepare 2-thienylmagnesium bromide. Take another 100mL Shrek bottle under inert gas protection and measure dichlorophenylphosphine (1.35mL, 10.0mmol) in 10mL of anhydrous tetrahydrofuran Medium. At -78 ℃, add 2-thiophene magnesium bromide Grignard reagent to the dichlorophenylphosphine solution through a double needle tip. After the addition is complete, wait for it to return to room temperature and stir for 2 hours to prepare benzene -(2-thienyl) phosphine chloride solution. Take another 100mL Shrek bottle, weigh it into lithium aluminum hydride (370mg, 10.0mmol), and inject 10mL of anhydrous tetrahydrofuran , Cooled to 0 ° C with ice water, the phenyl- (2-thienyl) phosphine chloride solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours. 5g of sodium sulfate decahydrate was added to stir to remove the residue The lithium tetrahydrogen aluminum, the solution was filtered through diatomaceous earth, dried after adding anhydrous sodium sulfate, and then transferred to another 100mL Shrek bottle that has been ventilated three times. Cool to -78 ° C, and add n-butadiene to it dropwise Lithium (4.38mL, 2.4M n-hexane solution, 10.5mmol), after 5 minutes of dripping, return to room temperature, and stir the reaction for 2 hours to prepare a phenyl- (2-thienyl) phosphine lithium solution. In a black bottle, weigh in methyl 2,3-anhydride-4,6-oxo-benzyl-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pump and ventilate three times, inject 10mL of tetrahydrofuran and stir to dissolve , The phenyl- (2-thienyl) phosphine lithium solution was dropped through the double needle tip, and the reaction was stirred for 6 hours. The reaction solution was added with 0.5mL of methanol under ice water bath, stirred for half an hour, the solvent was removed under reduced pressure, and 15mL of dichloromethane was added Dissolve the residue, and then wash the solution to neutrality with hydrochloric acid (1M, 15 mL), then wash the organic phase three times with saturated brine (20 mL), dry with anhydrous Nɑ 2 SO 4 , remove the solvent under reduced pressure, and use silica gel Separated and purified by column chromatography to obtain 3.7g Red foamy solid, yield 81%. mp: 70.2 ～ 73.0 ℃.
Figure PCTCN2019088461-appb-000041
(c 3.5, CH 2 Cl 2 ).
31P{ 1H}NMR(162MHz,CDCl 3)δ-32.50,-35.18。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-32.50, -35.18.
HRMS(ESI)理论值C 24H 25O 5PS+H +:457.1233.实测值:457.1230。 HRMS (ESI) theoretical value C 24 H 25 O 5 PS + H + : 457.1233. Found value: 457.1230.
实施例26.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-环己基-苯基膦-硼烷 Example 26. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azofyranosidyl-3) -cyclohexyl- Phenylphosphine-borane
Figure PCTCN2019088461-appb-000042
Figure PCTCN2019088461-appb-000042
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取环己基氯(1.18mL,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加剩余的四氢呋喃溶液,控制滴加速度以反应液保持微沸的状态下.滴加完毕后,65℃回流两小时.另取一100mL史莱克瓶,于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol),注入10mL的无水四氢呋喃.于-78℃下,将环己基氯化镁格氏试剂通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将苯基环己基氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液再氮气下通过硅藻土过滤,再加入无水硫酸钠干燥后,转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖将苯基环己基膦锂溶液转移至史莱克瓶中,搅拌反应6小时.反应液在冰水浴下加入0.5mL 甲醇,搅拌半小时,减压抽去溶剂,向残余物加入15mL二氯甲烷溶解,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,用无水Nɑ 2SO 4干燥,得到粗产品约4.6g.于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后搅拌3小时.减压抽去溶剂以及多余的硼烷,加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解残余物.产物经硅胶柱层析提纯,得到4.6g白色泡沫状固体,产率98％。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the activated magnesium scraps with a heated air gun for 15 minutes. After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure cyclohexyl chloride (1.18mL, 10.0mmol) and 10mL of anhydrous tetrahydrofuran to constant pressure For the funnel, add 0.5mL into a three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the remaining tetrahydrofuran solution to the three-necked bottle, and control the dripping rate to keep the reaction solution slightly boiling. After completion, reflux at 65 ℃ for two hours. Take another 100mL Shrek bottle, measure dichlorophenylphosphine (1.35mL, 10.0mmol) under the protection of inert gas, and inject 10mL of anhydrous tetrahydrofuran. At -78 ℃ , The cyclohexyl magnesium chloride Grignard reagent was added dropwise to the dichlorophenylphosphine solution through a double needle tip. After the addition was completed, wait for it to return to room temperature and stir for 2 hours. Take another 100mL Shrek bottle and weigh it into tetrahydrogen Lithium aluminum (370mg, 10.0mmol), inject 10mL of anhydrous tetrahydrofuran, and cool to 0 ° C with ice water, the phenylcyclohexylphosphine chloride solution The solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours. The residual lithium aluminum tetrahydrogen was removed with 5 g of sodium sulfate decahydrate, and the solution was filtered through celite under nitrogen, and dried over anhydrous sodium sulfate. After that, transfer to another 100 mL Shrek bottle that has been ventilated three times. Cool to -78 ° C, and add n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.5mmol) dropwise for 5 minutes. When finished, return to room temperature and stir the reaction for 2 hours. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4 g, 9.1 mmol), pumping and ventilating three times, injecting 10 mL of tetrahydrofuran with stirring and dissolving, transferring the phenylcyclohexylphosphine lithium solution to the Shrek via a double needle tip, and stirring for 6 hours. The reaction solution was added with 0.5 mL of methanol under an ice water bath , Stir for half an hour, remove the solvent under reduced pressure, add 15mL of dichloromethane to the residue to dissolve, then wash the solution to neutral with hydrochloric acid (1M, 15mL), then wash the organic phase three times with saturated brine (20mL), use dried over anhydrous Nɑ 2 SO 4, to obtain about 4.6 g of crude product. borane in tetrahydrofuran was added dropwise at -20 ℃ (1.0M, 11mL, 11mmol ), stirred back to room temperature for 3 hours under reduced pressure in order to take away the solvent The excess borane by adding 0.5mL of methanol, 15mL of dichloromethane was added to dissolve the residue. The product was purified by silica gel column chromatography, to give a white foamy solid 4.6g, 98% yield.
31P{ 1H}NMR(162MHz,CDCl 3)δ20.75,22.34。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 20.75, 22.34.
实施例27.(R p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-环己基苯基膦-硼烷 Example 27. (R p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -cyclohexyl Phenylphosphine-borane
Figure PCTCN2019088461-appb-000043
Figure PCTCN2019088461-appb-000043
称取(R p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-苯基环己基膦-硼烷(4.7g,10.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.65mL,10.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到4.7g白色固体混合物,产率98％。mp:157.9～160.3℃。 Weigh out (R p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -phenylcyclohexylphosphine-borane (4.7g , 10.0mmol) placed in a 50mL Shrek bottle, pumping and ventilating three times, injecting 10mL of anhydrous tetrahydrofuran, the mixture was cooled to 0 ℃ in an ice water bath, under the protection of inert gas was added NɑH (60% kerosene mixture, 400mg) stirred 1 After an hour, cool to -10 ° C with an ice / sodium chloride system, add iodomethane (0.65mL, 10.0mmol) dropwise, and stir the reaction for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 20mL of dichloromethane. Diatomaceous earth was filtered and purified by silica gel column chromatography to obtain 4.7g of white solid mixture with a yield of 98%. mp: 157.9 ～ 160.3 ℃.
1H NMR(400MHz,CDCl 3)δ7.86–7.70(m,2H),7.58(dd,J＝5.9,1.8Hz,2H),7.52–7.32(m,6H),5.53(s,1H),4.69–4.54(m,1H),4.47(s,1H),4.41–4.26(m,2H),3.68(t,J＝10.3Hz,1H),3.03(dd,J＝6.5,1.2Hz,1H),2.07(dt,J＝38.5,11.1Hz,3H),1.71–1.45(m,4H),1.33–0.73(m,7H),0.64(dd,J＝25.5,12.8Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.86–7.70 (m, 2H), 7.58 (dd, J = 5.9, 1.8 Hz, 2H), 7.52–7.32 (m, 6H), 5.53 (s, 1H), 4.69–4.54 (m, 1H), 4.47 (s, 1H), 4.41–4.26 (m, 2H), 3.68 (t, J = 10.3Hz, 1H), 3.03 (dd, J = 6.5, 1.2Hz, 1H) , 2.07 (dt, J = 38.5, 11.1 Hz, 3H), 1.71-1.45 (m, 4H), 1.33-0.73 (m, 7H), 0.64 (dd, J = 25.5, 12.8 Hz, 1H).
13C NMR(101MHz,CDCl 3)δ137.50,133.68,131.13,129.12,128.71,128.05,127.45,126.84,102.74,97.28,78.59,77.37,77.10,76.89,76.12,69.52,59.86,57.82,53.66,37.64 37.32,34.44,34.20,27.75,27.42,27.39,26.73,25.93。 13 C NMR (101 MHz, CDCl 3 ) δ 137.50, 133.68, 131.13, 129.12, 128.71, 128.05, 127.45, 126.84, 102.74, 97.28, 78.59, 77.37, 77.10, 76.89, 76.12, 69.52, 59.86, 57.82, 53.66, 37.64 37.32, 34.44, 34.20, 27.75, 27.42, 27.39, 26.73, 25.93.
31P{ 1H}NMR(162MHz,CDCl 3)δ22.55。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 22.55.
实施例28.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-(2-萘基)-苯基膦 Example 28. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3)-(2- Naphthyl) -phenylphosphine
Figure PCTCN2019088461-appb-000044
Figure PCTCN2019088461-appb-000044
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.称取2-溴萘(2.00g,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加剩余的四氢呋喃溶液,控制滴加速度使反应液始终保持微沸状态.滴加完毕后,65℃回流两小时制得2-萘溴化镁,冷至室温待用.另取一个100mL史莱克瓶,于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol),注入10mL的无水四氢呋喃.于-78℃下,将2-萘溴化镁通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时制得苯基-(2-萘基)氯化膦.另取一个100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将苯基-2-萘基氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液再在氮气下通过硅藻土过滤,加入无水硫酸钠干燥后,转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,搅拌反应2小时.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入苯基-(2-萘基)膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Nɑ 2SO 4干燥,减压抽除溶剂.产物经硅胶柱层析分离提纯,得到4.1g白色泡沫状固体,产率78％。mp:92.4～94.8℃。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Pump to vacuum, heat the activated magnesium scraps with a heated air gun for 15 minutes, wait for the three-necked bottle to cool to room temperature, and fill it with nitrogen. Weigh 2-bromonaphthalene (2.00g, 10.0mmol) and 10mL of anhydrous tetrahydrofuran into a constant pressure funnel , Add 0.5mL into a three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the remaining tetrahydrofuran solution to the three-necked bottle, and control the dripping rate to keep the reaction solution slightly boiling. , 2-naphthylmagnesium bromide was prepared by refluxing at 65 ℃ for two hours, and cooled to room temperature for use. Another 100mL Shrek bottle was taken, and dichlorophenylphosphine (1.35mL, 10.0mmol) was measured under inert gas protection. Inject 10mL of anhydrous tetrahydrofuran. At -78 ° C, add 2-naphthalene bromide to the dichlorophenylphosphine solution through a double needle drop. After the addition is complete, wait for it to return to room temperature and stir for 2 hours to prepare Obtain phenyl- (2-naphthyl) phosphine chloride. Take another 100mL Shrek bottle, weigh it into lithium aluminum hydride (370mg, 10.0mmol), inject 10mL of anhydrous tetrahydrofuran, and use ice water At 0 ° C, the phenyl-2-naphthylphosphine chloride solution was added dropwise to the lithium aluminum hydride solution through a double needle tip, and the reaction was stirred for 2 hours. The residual lithium aluminum hydride was removed with 5 g of sodium sulfate decahydrate, the solution Filter through diatomaceous earth under nitrogen, add anhydrous sodium sulfate to dry, transfer to another 100mL Shrek bottle that has been ventilated three times. Cool to -78 ° C, and add n-butyl lithium (4.38) dropwise to it mL, 2.4M n-hexane solution, 10.5mmol), after about 5 minutes of dripping, return to room temperature and stir the reaction for 2 hours. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6- Oxy-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, and adding a phenyl- (2-naphthyl) phosphine lithium solution through a double needle tip , Stir the reaction for 6 hours. Add 0.5 mL of methanol to the reaction solution under ice-water bath, stir for half an hour, remove the solvent under reduced pressure, add 15 mL of dichloromethane to dissolve the residue, and then wash the solution to neutrality with hydrochloric acid (1 M, 15 mL). Then, the organic phase was washed three times with saturated brine (20 mL), dried over anhydrous Nɑ 2 SO 4 , and the solvent was removed under reduced pressure. The product was separated and purified by silica gel column chromatography to obtain 4.1 g of white foamy solid with a yield of 78%. mp: 92.4 ～ 94.8 ℃.
Figure PCTCN2019088461-appb-000045
(c 2.5,CH 2Cl 2).
Figure PCTCN2019088461-appb-000045
(c 2.5, CH 2 Cl 2 ).
31P{ 1H}NMR(162MHz,CDCl 3)δ-12.79,-21.29。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-12.79, -21.29.
实施例29.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔 丁基膦-硼烷 Example 29. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3) -tert-butyl Phosphine-borane
Figure PCTCN2019088461-appb-000046
Figure PCTCN2019088461-appb-000046
在惰性气体保护下称取(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦(3.5g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后搅拌3小时.减压抽去溶剂以及多余的硼烷,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解.产物经短硅胶柱提纯,得到3.1g白色泡沫状固体,产率84％。 Weigh (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyranoglycosyl-3)-under inert gas protection Tert-butylphosphine (3.5g, 10mmol), add borane solution in tetrahydrofuran (1.0M, 11mL, 11mmol) dropwise at -20 ℃, return to room temperature and stir for 3 hours. Remove the solvent and excess borane under reduced pressure , The residue was added 0.5mL of methanol, and then added 15mL of methylene chloride to dissolve. The product was purified by a short silica gel column to obtain 3.1g of white foamy solid, yield 84%.
31P{ 1H}NMR(162MHz,CDCl 3)δ26.66,15.04。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 26.66, 15.04.
实施例30.(R p)-和(S p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基甲基膦-硼烷 Example 30. (R p )-and (S p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide -3) -tert-butylmethylphosphine-borane
Figure PCTCN2019088461-appb-000047
Figure PCTCN2019088461-appb-000047
称取(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦-硼烷混合物(3.7g,10.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.65mL,20.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到3.6g白色固体,得到0.7g的(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦-硼烷,2.9g的(R p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦-硼烷,总产率90％。 Weigh out (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -tert-butylphosphine- The borane mixture (3.7g, 10.0mmol) was placed in a 50mL Shrek bottle, pumped and ventilated three times, infused with 10mL of anhydrous tetrahydrofuran, and the mixture was cooled to 0 ° C in an ice water bath. Mixture, 400mg) After stirring for 1 hour, it was cooled to -10 ° C with an ice / sodium chloride system, iodomethane (0.65mL, 20.0mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was taken with 20mL The methyl chloride was dissolved, filtered through diatomaceous earth, and purified by silica gel column chromatography to obtain 3.6 g of white solid, and 0.7 g of (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene) -ɑ-D-Aranopyranoside-3) -tert-butylphosphine-borane, 2.9g of (R p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ -D-Aranopyranoside-3) -tert-butylphosphine-borane, total yield 90%.
(R p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基甲基膦-硼烷 (R p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -tert-butylmethylphosphine-boron alkyl
1H NMR(400MHz,CDCl 3)δ7.42(dd,J＝6.0,2.5Hz,2H),7.37–7.28(m,3H),5.51(s,1H),4.65(s,1H),4.41–4.24(m,2H),4.19(d,J＝6.7Hz,1H),4.01(td,J＝ 10.1,5.0Hz,1H),3.71(t,J＝10.3Hz,1H),2.74(dd,J＝12.3,7.2Hz,1H),1.55(d,J＝10.6Hz,3H),1.08(d,J＝13.6Hz,9H),0.88–0.15(m,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (dd, J = 6.0, 2.5 Hz, 2H), 7.37–7.28 (m, 3H), 5.51 (s, 1H), 4.65 (s, 1H), 4.41– 4.24 (m, 2H), 4.19 (d, J = 6.7 Hz, 1H), 4.01 (td, J = 10.1, 5.0 Hz, 1H), 3.71 (t, J = 10.3 Hz, 1H), 2.74 (dd, J = 12.3, 7.2 Hz, 1H), 1.55 (d, J = 10.6 Hz, 3H), 1.08 (d, J = 13.6 Hz, 9H), 0.88-0.15 (m, 3H).
13C NMR(101MHz,CDCl 3)δ137.01,129.23,128.26,126.35,103.05,97.94,78.68(d,J＝8.0Hz),76.24(d,J＝7.1Hz),69.78,60.37,57.91,54.58,31.90(d,J＝19.4Hz),30.03,29.70,26.86(d,J＝2.1Hz),5.98,5.66。 13 C NMR (101 MHz, CDCl 3 ) δ 137.01, 129.23, 128.26, 126.35, 103.05, 97.94, 78.68 (d, J = 8.0 Hz), 76.24 (d, J = 7.1 Hz), 69.78, 60.37, 57.91, 54.58, 31.90 (d, J = 19.4 Hz), 30.03, 29.70, 26.86 (d, J = 2.1 Hz), 5.98, 5.66.
31P{ 1H}NMR(162MHz,CDCl 3)δ33.91。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 33.91.
HRMS(ESI)理论值C 20H 34BO 5P+H +:397.2313.实测值:397.2310。 HRMS (ESI) theoretical value C 20 H 34 BO 5 P + H + : 397.2313. Found value: 397.2310.
(S p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基甲基膦-硼烷 (S p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -tert-butylmethylphosphine-boron alkyl
mp:190.3～192.6℃。
Figure PCTCN2019088461-appb-000048
(c 1.1,CH 2Cl 2)。 mp: 190.3 ～ 192.6 ℃.
Figure PCTCN2019088461-appb-000048
(c 1.1, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.63–7.53(m,2H),7.37–7.27(m,3H),5.47(s,1H),4.73–4.60(m,2H),4.24(ddd,J＝23.6,10.2,5.8Hz,2H),3.66(t,J＝10.4Hz,1H),3.49(d,J＝4.4Hz,1H),3.46(s,3H),3.41(s,3H),2.87(dd,J＝13.3,6.1Hz,1H),1.62(s,1H),1.40(d,J＝9.4Hz,3H),1.08(d,J＝13.3Hz,12H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.63–7.53 (m, 2H), 7.37–7.27 (m, 3H), 5.47 (s, 1H), 4.73–4.60 (m, 2H), 4.24 (ddd, J = 23.6, 10.2, 5.8 Hz, 2H), 3.66 (t, J = 10.4 Hz, 1H), 3.49 (d, J = 4.4 Hz, 1H), 3.46 (s, 3H), 3.41 (s, 3H), 2.87 (dd, J = 13.3, 6.1 Hz, 1H), 1.62 (s, 1H), 1.40 (d, J = 9.4 Hz, 3H), 1.08 (d, J = 13.3 Hz, 12H).
13C NMR(101MHz,CDCl 3)δ137.34,129.04,128.07,127.12,103.45,96.89,78.99,77.38,77.06,76.75,75.32,69.53,59.85,58.15,53.79,31.46,30.14,29.82,26.17,7.36,7.02。 13 C NMR (101 MHz, CDCl 3 ) δ 137.34, 129.04, 128.07, 127.12, 103.45, 96.89, 78.99, 77.38, 77.06, 76.75, 75.32, 69.53, 59.85, 58.15, 53.79, 31.46, 30.14, 29.82, 26.17, 7.36, 7.02 .
31P{ 1H}NMR(162MHz,CDCl 3)δ26.27。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 26.27.
HRMS(ESI)理论值C 20H 34BO 5P+Na +:419.2191.实测值:419.2124。 HRMS (ESI) theoretical value C 20 H 34 BO 5 P + Na + : 419.2191. Found: 419.2124.
实施例31.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基膦 Example 31. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3) -ferrocene Phosphine
Figure PCTCN2019088461-appb-000049
Figure PCTCN2019088461-appb-000049
在惰性气体保护下中将二茂铁膦(1.0g,4.6mmol)与10mL四氢呋喃置于50mL史莱克瓶,于-78℃下滴加正丁基锂(2.2mL,2.4M的正己烷溶液,5.3mmol),约5分钟滴完,回至室温,搅拌反应2小时制得二茂铁膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(1.2g,4.6mmol), 抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入二茂铁膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,分离出有机相,无水Nɑ 2SO 4干燥,减压抽除溶剂.混合物用甲醇重结晶,得到1.91g橙红色固体,产率85％。 Under the protection of inert gas, put ferrocenephosphine (1.0g, 4.6mmol) and 10mL tetrahydrofuran in a 50mL Shrek bottle, and drop n-butyllithium (2.2mL, 2.4M n-hexane solution at -78 ° C, 5.3mmol), about 5 minutes after the completion of the drop, return to room temperature, stir the reaction for 2 hours to prepare a ferrocene phosphonium lithium solution. Take another 50mL Shrek bottle, weighed methyl 2,3-anhydride-4,6-oxo -Benzylidene-ɑ-D-mannopyranoside (1.2g, 4.6mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add lithium ferrocenephosphine solution through a double needle tip, and stir to react for 6 hours. The solution was added with 0.5 mL of methanol under ice water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and the solution was washed with saturated ammonium chloride, the organic phase was separated, anhydrous Nɑ 2 SO 4 After drying, the solvent was removed under reduced pressure. The mixture was recrystallized from methanol to obtain 1.91 g of orange-red solid with a yield of 85%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-72.49,-80.22。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-72.49, -80.22.
实施例32.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基膦-硼烷 Example 32. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azofyranoside-3) -ferrocene Phosphine-borane
Figure PCTCN2019088461-appb-000050
Figure PCTCN2019088461-appb-000050
在惰性气体保护下称取(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基膦(964mg,2.0mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,3.0mL,3.0mmol),回至室温后搅拌3小时.减压抽去溶剂以及多余的硼烷,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解.产物经短硅胶柱进行提纯,得到966mg橙红色泡沫状固体,产率97％。 Weigh (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyranoglycosyl-3)-under inert gas protection Ferrocenylphosphine (964mg, 2.0mmol) was added dropwise a solution of borane in tetrahydrofuran (1.0M, 3.0mL, 3.0mmol) at -20 ℃, and returned to room temperature and stirred for 3 hours. The solvent and excess were removed under reduced pressure The borane, the residue was added 0.5mL of methanol, and then added 15mL of dichloromethane to dissolve. The product was purified by a short silica gel column to obtain 966mg orange-red foamy solid, yield 97%.
31P{ 1H}NMR(162MHz,CDCl 3)δ18.91,14.73。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ 18.91, 14.73.
实施例33.(R p)-和(S p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基甲基膦-硼烷 Example 33. (R p )-and (S p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azrenoside -3) -Ferrocenemethylphosphine-borane
Figure PCTCN2019088461-appb-000051
Figure PCTCN2019088461-appb-000051
称取(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基膦-硼烷(496mg,1.0mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NɑH(60％的煤油混合物,40mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷 (0.7mL,2.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,共得到473mg橙红色固体,其中(R p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基-甲基膦-硼烷9mg,(S p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基甲基膦-硼烷464mg,总产率90％。 Weigh out (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -ferrocenylphosphine -Borane (496mg, 1.0mmol) was placed in a 50mL Shrek bottle, pumped and ventilated three times, infused with 10mL of anhydrous tetrahydrofuran, the mixture was cooled to 0 ° C in an ice water bath, and NɑH (60% kerosene mixture) was added under the protection of inert gas , 40mg) After stirring for 1 hour, it was cooled to -10 ° C with an ice / sodium chloride system, iodomethane (0.7mL, 2.0mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was taken with 20mL of dichloromethane Methane is dissolved, then filtered through diatomaceous earth, and purified by silica gel column chromatography. A total of 473 mg of orange-red solid is obtained, in which (R p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo- Benzylidene-ɑ-D-pyrandrosyl glycoside-3) -ferrocenyl-methylphosphine-borane 9mg, (S p )-(methyl 2-oxo-methyl-3-deoxy -4,6-Oxyl-benzylidene-ɑ-D-pyranopyranosidyl-3) -ferrocenylmethylphosphine-borane 464mg, total yield 90%.
(R p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基甲基膦-硼烷 (R p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -ferrocenylmethyl Phosphine-borane
1H NMR(400MHz,CDCl 3)δ7.47(dd,J＝48.6,3.8Hz,5H),5.50(s,1H),4.64(s,1H),4.58(s,1H),4.44(s,1H),4.38–4.19(m,8H),4.09(s,1H),3.71(t,J＝9.9Hz,1H),3.59–3.15(m,7H),2.63(dd,J＝14.3,6.0Hz,1H),1.81(d,J＝10.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (dd, J = 48.6, 3.8 Hz, 5H), 5.50 (s, 1H), 4.64 (s, 1H), 4.58 (s, 1H), 4.44 (s, 1H), 4.38–4.19 (m, 8H), 4.09 (s, 1H), 3.71 (t, J = 9.9Hz, 1H), 3.59–3.15 (m, 7H), 2.63 (dd, J = 14.3, 6.0Hz) , 1H), 1.81 (d, J = 10.6 Hz, 3H).
31P{ 1H}NMR(162MHz,CDCl 3)δ11.11。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 11.11.
(S p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二茂铁基-甲基膦-硼烷 (S p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -ferrocenyl-methyl Phosphine-borane
mp:156.3～158.1℃。mp: 156.3 ～ 158.1 ℃.
1H NMR(400MHz,CDCl 3)δ7.49(dt,J＝13.9,6.7Hz,5H),5.51(s,1H),4.73(s,1H),4.59–4.18(m,11H),4.09–3.96(m,2H),3.67–3.41(m,4H),3.21(td,J＝10.0,5.2Hz,1H),3.11(s,3H),2.74–2.52(m,1H),1.82(d,J＝10.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (dt, J = 13.9, 6.7 Hz, 5H), 5.51 (s, 1H), 4.73 (s, 1H), 4.59–4.18 (m, 11H), 4.09– 3.96 (m, 2H), 3.67–3.41 (m, 4H), 3.21 (td, J = 10.0, 5.2Hz, 1H), 3.11 (s, 3H), 2.74–2.52 (m, 1H), 1.82 (d, J = 10.2 Hz, 3H).
13C NMR(101MHz,CDCl 3)δ137.56,128.93,128.39,125.91,102.03,98.07,78.14,77.33,77.25,76.17,72.53,70.93,70.43,70.00,69.80,69.42,67.49,58.80,57.72,53.72,39.68,14.81。 13 C NMR (101 MHz, CDCl 3 ) δ 137.56, 128.93, 128.39, 125.91, 102.03, 98.07, 78.14, 77.33, 77.25, 76.17, 72.53, 70.93, 70.43, 70.00, 69.80, 69.42, 67.49, 58.80, 57.72, 53.72, 39.68 , 14.81.
31P{ 1H}NMR(162MHz,CDCl 3)δ8.99。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 8.99.
HRMS(ESI)理论值C 26H 34BFeO 5P:524.1586.实测值:524.1597。 HRMS (ESI) theoretical value C 26 H 34 BFeO 5 P: 524.1586. Found value: 524.1597.
实施例34.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-(2-甲苯基)膦 Example 34. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3)-(2- Tolyl) phosphine
Figure PCTCN2019088461-appb-000052
Figure PCTCN2019088461-appb-000052
在惰性气体保护下中将2-甲基苯基膦(1.1g,10.0mmol)与10mL四氢呋喃置 于50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.6mmol),约5分钟滴完,回至室温,搅拌反应2小时制得2-甲基苯基膦锂溶液.另取一100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入二茂铁膦锂溶液,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,分离出有机相,无水Nɑ 2SO 4干燥,减压抽除溶剂.混合物用甲醇重结晶,得到3.3g为白色固体的(Rp)-和(Sp)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-(2-甲苯基)膦混合物,产率85％。 Place 2-methylphenylphosphine (1.1g, 10.0mmol) and 10mL tetrahydrofuran in a 50mL Shrek bottle under inert gas protection, and add n-butyllithium (4.4mL, 2.4M n-hexane) dropwise at -78 ℃ Alkane solution, 10.6 mmol), after about 5 minutes of dripping, return to room temperature, stir the reaction for 2 hours to prepare a 2-methylphenylphosphine lithium solution. Take another 100mL Shrek bottle and weigh into methyl 2,3-anhydride -4,6-Oxyl-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, and adding the ferrocenephosphine lithium solution through the double needle tip, The reaction was stirred for 6 hours. The reaction solution was added with 0.5 mL of methanol under ice-water bath, stirred for half an hour, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and the solution was washed with saturated ammonium chloride, and the organic phase was separated, Anhydrous Nɑ 2 SO 4 was dried, and the solvent was removed under reduced pressure. The mixture was recrystallized from methanol to obtain 3.3 g of (Rp)-and (Sp)-(methyl 3-deoxy-4,6-oxo-benzene) as white solids. Methylene-ɑ-D-azopyranoside-3)-(2-tolyl) phosphine mixture, yield 85%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-68.16,-73.19。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-68.16, -73.19.
实施例35.(R p)-和(S p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦 Example 35. (R p )-and (S p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-3) -tert-butyl phosphine
Figure PCTCN2019088461-appb-000053
Figure PCTCN2019088461-appb-000053
在惰性气体保护下中量取叔丁基膦(1.2mL,10.0mmol)入50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,搅拌反应2小时制得叔丁基膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入叔丁基膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵将溶液洗涤,分离出有机相,无水Nɑ 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.2g白色固体,产率90％。 Measure t-butylphosphine (1.2mL, 10.0mmol) into a 50mL Shrek bottle under inert gas protection, and add n-butyllithium (4.4mL, 2.4M n-hexane solution, 10.5mmol) dropwise at -78 ℃ After about 5 minutes of dripping, return to room temperature and stir the reaction for 2 hours to prepare a lithium tert-butylphosphonate solution. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzoic acid Forkyl-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, adding lithium tert-butylphosphonate solution through a double needle tip, stirring and reacting for 6 hours. Add under ice water bath 0.5mL of methanol, stirred for half an hour, the solvent was removed under reduced pressure, 15mL of dichloromethane was added to dissolve the residue, the solution was washed with saturated ammonium chloride, the organic phase was separated, dried with anhydrous Nɑ 2 SO 4 and removed under reduced pressure Solvent. The residue was recrystallized from methanol to obtain 3.2 g of white solid with a yield of 90%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-26.20,-40.65。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-26.20, -40.65.
实施例36.(R p)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷-3)-叔丁基硫化膦 Example 36. (R p )-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azorranoside-3) -tert-butylphosphine sulfide
Figure PCTCN2019088461-appb-000054
Figure PCTCN2019088461-appb-000054
在惰性气体保护下称取(S p)-(甲基3-脱氧-4,6-氧-苯基甲叉基-ɑ-D-吡喃阿卓糖苷-3)-叔丁基膦(100mg,2.8mmol)置于25mL史莱克瓶中,注入5mL氯仿,加入S 8(90mg,2.8mmol),加热回流6h.反应液冷至室温,过滤,抽除溶剂,得到0.9g白色固体,产率83％。 Weigh (S p )-(methyl 3-deoxy-4,6-oxo-phenylmethylidene-ɑ-D-pyranoside-3) -tert-butylphosphine (100mg) under the protection of inert gas , 2.8mmol) placed in a 25mL Shrek bottle, inject 5mL of chloroform, add S 8 (90mg, 2.8mmol), heated to reflux for 6h. The reaction solution was cooled to room temperature, filtered, and the solvent was removed to give 0.9g white solid, yield 83%.
31P{ 1H}NMR(162MHz,CDCl 3)δ62.37。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 62.37.
实施例37.(R p)-(甲基3-脱氧-4,6-氧-苯基甲叉基-ɑ-D-吡喃阿卓糖苷-3)-叔丁基氧膦 Example 37. (R p )-(methyl 3-deoxy-4,6-oxo-phenylmethylidene-ɑ-D-azorranoside-3) -tert-butylphosphine oxide
Figure PCTCN2019088461-appb-000055
Figure PCTCN2019088461-appb-000055
在惰性气体保护下称取(S p)-(甲基3-脱氧-4,6-氧-苯基甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-叔丁基膦(100mg,2.8mmol)置于25mL史莱克瓶中,注入5mL氯仿,在空气中加热回流6h.反应液冷至室温,过滤,抽除溶剂,得到0.9g白色固体,产率83％。 Weigh (S p )-(methyl 3-deoxy-4,6-oxo-phenylmethylidene-ɑ-D-pyranoglycosyl-3) -tert-butylphosphine under the protection of inert gas ( 100mg, 2.8mmol) was placed in a 25mL Shrek bottle, injected with 5mL chloroform, heated to reflux in the air for 6h. The reaction solution was cooled to room temperature, filtered, and the solvent was removed to obtain 0.9g white solid with a yield of 83%.
31P{ 1H}NMR(162MHz,CDCl 3)δ52.38。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 52.38.
实施例38.(R p)-(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-2-联苯基膦 Example 38. (R p )-(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -2- Biphenylphosphine
Figure PCTCN2019088461-appb-000056
Figure PCTCN2019088461-appb-000056
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.量取2-溴联苯(2.3g,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回流两小 时.另取一100mL史莱克瓶,于惰性气体保护下中量取三氯化磷(0.67g,10.0mmol),注入10mL的无水四氢呋喃.于-78℃下,将2-联苯溴化镁格氏试剂通过双针尖滴加至三氯化磷溶液中,滴加完毕后,待其回到-40℃,搅拌反应2小时.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水乙醚,用冰水冷至0℃,将2-联苯基氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液在氮气下通过硅藻土过滤,再加入无水硫酸钠干燥后,转移至另一已抽换气三次的50mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.6mmol),5分钟滴完,回至室温,搅拌反应1小时.另取一100mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(1.2g,4.5mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入上面制备的2-联苯基膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,向残余物加入15mL二氯甲烷溶解,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Na 2SO 4干燥,减压抽除溶剂,乙醇重结晶,得到白色固体,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.13mL,5.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.4g白色固体,产率63％。mp:198～200℃。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Pump to a vacuum state, heat the activated magnesium scraps with a heated air gun for 15 minutes, and after the three-necked bottle is cooled to room temperature, fill it with nitrogen. Take 2-bromobiphenyl (2.3g, 10.0mmol) and 10mL of anhydrous tetrahydrofuran to constant pressure For the funnel, add 0.5mL into the three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the tetrahydrofuran solution to the three-necked bottle to control the dripping rate so that the reaction solution maintains a slightly boiling state. Reflux at 65 ℃ for two hours. Take another 100mL Shrek bottle, measure phosphorus trichloride (0.67g, 10.0mmol) under the protection of inert gas, and inject 10mL of anhydrous tetrahydrofuran. At -78 ℃, transfer 2- The biphenyl magnesium bromide Grignard reagent was added dropwise to the phosphorus trichloride solution through a double needle tip. After the addition was completed, wait for it to return to -40 ° C and stir to react for 2 hours. Take another 100mL Shrek bottle and weigh into four Lithium aluminum hydride (370mg, 10.0mmol), inject 10mL of anhydrous ether, cool to 0 ° C with ice water, add 2-biphenylphosphine chloride solution dropwise to the lithium tetrahydrogen solution through a double needle tip , Stir the reaction for 2 hours. Use 5g of sodium sulfate decahydrate to remove the residual lithium aluminum hydride. The solution was filtered through diatomaceous earth under nitrogen. After adding anhydrous sodium sulfate to dry, the solution was transferred to another pumped and ventilated three times. 50mL Shrek bottle. Cooled to -78 ℃, to which n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.6mmol) was added dropwise, after 5 minutes of dripping, returned to room temperature, and stirred to react for 1 hour. Take a 100mL Shrek bottle, weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (1.2g, 4.5mmol), pump and ventilate three times, inject 10mL of tetrahydrofuran was stirred and dissolved, and the 2-biphenylphosphine lithium solution prepared above was added through a double needle tip, and the reaction was stirred for 6 hours. 0.5mL of methanol was added under an ice water bath, stirred for half an hour, the solvent was removed under reduced pressure, and 15mL of 2 was added to the residue Chloromethane was dissolved, and then the solution was washed with hydrochloric acid (1M, 15mL) to neutrality, and then the organic phase was washed three times with saturated brine (20mL), dried over anhydrous Na 2 SO 4 , the solvent was removed under reduced pressure, and ethanol was recrystallized, A white solid was obtained, poured into 10mL of anhydrous tetrahydrofuran, the mixture was cooled to 0 ° C in an ice-water bath, and NaH (60% kerosene mixture, 400mg) was added under an inert gas atmosphere and stirred for 1 hour. The sodium hydroxide system was cooled to -10 ° C, methyl iodide (0.13mL, 5.0mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20mL of dichloromethane, and then filtered through celite, silica gel column Chromatographic separation and purification gave 1.4g white solid with a yield of 63%. mp: 198 ～ 200 ℃.
1H NMR(400MHz,CDCl 3)δ8.01(dd,J＝7.5,3.5Hz,1H),7.91(d,J＝7.6Hz,1H),7.82(d,J＝7.7Hz,1H),7.69–7.58(m,3H),7.46(d,J＝5.4Hz,4H),7.37–7.27(m,3H),7.19(d,J＝7.2Hz,1H),6.87(t,J＝6.5Hz,1H),5.68(s,1H),5.36(s,1H),4.84–4.73(m,2H),4.41(ddd,J＝14.6,9.9,5.2Hz,2H),4.30–4.15(m,1H),4.07(d,J＝5.9Hz,1H),3.91(t,J＝10.3Hz,1H),3.62(d,J＝10.3Hz,3H),3.59(d,J＝4.1Hz,1H),3.37(s,1H),3.05(s,3H),2.40(d,J＝5.4Hz,1H),1.63(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (dd, J = 7.5, 3.5 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 –7.58 (m, 3H), 7.46 (d, J = 5.4Hz, 4H), 7.37–7.27 (m, 3H), 7.19 (d, J = 7.2Hz, 1H), 6.87 (t, J = 6.5Hz, 1H), 5.68 (s, 1H), 5.36 (s, 1H), 4.84–4.73 (m, 2H), 4.41 (ddd, J = 14.6, 9.9, 5.2Hz, 2H), 4.30–4.15 (m, 1H) , 4.07 (d, J = 5.9 Hz, 1H), 3.91 (t, J = 10.3 Hz, 1H), 3.62 (d, J = 10.3 Hz, 3H), 3.59 (d, J = 4.1 Hz, 1H), 3.37 (s, 1H), 3.05 (s, 3H), 2.40 (d, J = 5.4 Hz, 1H), 1.63 (s, 1H).
31P{ 1H}NMR(162MHz,CDCl 3)δ-17.12。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-17.12.
HRMS(ESI)理论值C 27H 29O 5P+H +:463.1668.实测值:463.1662。 HRMS (ESI) theoretical value C 27 H 29 O 5 P + H + : 463.1668. Found: 463.1662.
实施例39.(Rp)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-2-联苯基-苯基膦Example 39. (Rp)-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -2-biphenyl-phenylphosphine
Figure PCTCN2019088461-appb-000057
Figure PCTCN2019088461-appb-000057
在压力管中,在氮气氛围下,分别称入(Rp)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-2-苯基膦(374mg,1.0mmol)、2-溴联苯(256mg,1.1mmol)和叔丁醇钠(115mg,1.2mmol)，注入提前混合好的醋酸钯(4.5mg,2mol％)与Dippf(12.0mg,2mol％)的甲苯溶液，加入1.0mL的甲苯，100℃下反应12h。加入二氯甲烷并硅藻土助滤.。通过(二氯甲烷/甲醇)柱层析分离得到(Rp)-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-2-联苯基-苯基膦411mg，产率78％。In a pressure tube, under a nitrogen atmosphere, weigh (Rp)-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -2 -Phenylphosphine (374mg, 1.0mmol), 2-bromobiphenyl (256mg, 1.1mmol) and sodium tert-butoxide (115mg, 1.2mmol), injected with pre-mixed palladium acetate (4.5mg, 2mol%) and Dippf (12.0mg, 2mol%) toluene solution, add 1.0mL of toluene, and react at 100 ° C for 12h. Add dichloromethane and filter through celite. (Rp)-(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -2 was separated by (dichloromethane / methanol) column chromatography -Biphenyl-phenylphosphine 411 mg, yield 78%.
31P{1H}NMR(162MHz,CDCl 3)δ-32.30。 31 P {1H} NMR (162 MHz, CDCl 3 ) δ-32.30.
实施例40.(苯基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦-硼烷Example 40. (Phenyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000058
Figure PCTCN2019088461-appb-000058
在惰性气体保护下中量取二环己基膦(2.0mL,10.0mmol)加入50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时.另取一个50mL史莱克瓶,称入苯基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.9g,9.0mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖将二环己基膦锂溶液转移至史莱克瓶中,搅拌反应6小时.于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后搅拌3小时.减压抽去溶剂以及多余的硼烷,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,经过短硅胶柱提纯.冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(1.17mL,9.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提 纯,混合物用硅胶柱层析分离,得到4.1g白色固体,产率82％。mp:190.9～193.6℃。
Figure PCTCN2019088461-appb-000059
(c1.5,CH 2Cl 2)。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) was weighed into a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane solution, 10.5mmol) was added dropwise at -78 ° C. After 5 minutes of dripping, return to room temperature and stir the reaction for 2 hours. Take another 50mL Shrek bottle and weigh it into phenyl 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-pyran Mannoside (2.9g, 9.0mmol), pumped and ventilated three times, inject 10mL of tetrahydrofuran with stirring to dissolve, transfer the dicyclohexylphosphine lithium solution to the Shrek via a double needle tip at room temperature, and stir to react for 6 hours at -20 ℃ A solution of borane in tetrahydrofuran (1.0 M, 11 mL, 11 mmol) was added dropwise, and the mixture was returned to room temperature and stirred for 3 hours. The solvent and excess borane were removed under reduced pressure, and 0.5 mL of methanol was added to the residue, followed by 15 mL of dichloromethane Methane is dissolved and purified through a short silica gel column. The mixture is cooled to 0 ° C in an ice-water bath, NaH (60% kerosene mixture, 400 mg) is added under an inert gas atmosphere, stirred for 1 hour, and cooled to -10 with an ice / sodium chloride system Iodomethane (1.17mL, 9.0mmol) was added dropwise and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 20mL of dichloromethane, then filtered through celite, and purified by silica gel column chromatography. It was chromatographed on a silica gel column, to give 4.1g white solid in 82% yield. mp: 190.9 ～ 193.6 ℃.
Figure PCTCN2019088461-appb-000059
(c1.5, CH 2 Cl 2 ).
1H NMR(400MHz,CDCl 3)δ7.48–7.27(m,7H),7.08(dd,J＝17.7,7.8Hz,3H),5.60(s,1H),5.45(s,1H),4.50–4.39(m,1H),4.37–4.22(m,2H),4.04(td,J＝10.0,5.1Hz,1H),3.76(t,J＝10.2Hz,1H),3.49(s,3H),2.98(dd,J＝12.1,7.1Hz,1H),2.79(q,J＝12.2Hz,1H),2.56(d,J＝12.5Hz,1H),2.45–2.27(m,2H),2.09–0.88(m,22H),0.68(dd,J＝131.0,54.1Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48–7.27 (m, 7H), 7.08 (dd, J = 17.7, 7.8 Hz, 3H), 5.60 (s, 1H), 5.45 (s, 1H), 4.50– 4.39 (m, 1H), 4.37–4.22 (m, 2H), 4.04 (td, J = 10.0, 5.1 Hz, 1H), 3.76 (t, J = 10.2 Hz, 1H), 3.49 (s, 3H), 2.98 (dd, J = 12.1, 7.1 Hz, 1H), 2.79 (q, J = 12.2 Hz, 1H), 2.56 (d, J = 12.5 Hz, 1H), 2.45-2.27 (m, 2H), 2.09-0.88 ( m, 22H), 0.68 (dd, J = 131.0, 54.1 Hz, 3H).
13C NMR(101MHz,CDCl 3)δ156.34,137.17,129.74,129.12,128.22,125.96,122.73,116.53,102.44,96.98,78.15,78.08,77.19,77.11,69.71,61.34,57.77,34.11,33.91,31.70,31.63,31.44,31.31,30.31,28.74,28.22,28.08,27.71,27.64,27.28,27.20,26.83,26.77,26.71,26.64,26.06,25.89。 13 C NMR (101 MHz, CDCl 3 ) δ156.34,137.17,129.74,129.12,128.22,125.96,122.73,116.53,102.44,96.98,78.15,78.08,77.19,77.11,69.71,61.34,57.77,34.11,33.91,31.70,3163 , 31.44,31.31,30.31,28.74,28.22,28.08,27.71,27.64,27.28,27.20,26.83,26.77,26.71,26.64,26.06,25.89.
31P{ 1H}NMR(162MHz,CDCl 3)δ34.05。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 34.05.
HRMS(ESI)理论值C 32H 46BO 5P+Na +:575.3074.实测值:575.3139。 HRMS (ESI) theoretical value C 32 H 46 BO 5 P + Na + : 575.3074. Found: 575.3139.
实施例41.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 41. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000060
Figure PCTCN2019088461-appb-000060
在惰性气体保护下中将二环己基膦(2.0mL,10.0mmol)加入50mL史莱克瓶,加入10mL新蒸四氢呋喃.于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,反应液搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-异丙叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,该溶液在室温下通过双针尖加入二环己基膦锂溶液,反应液搅拌反应6小时.冰水浴下加入0.5mL甲醇,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,有机相用饱和氯化铵溶液洗涤，无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.3g白色固体,产率77％。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) was added to a 50mL Shrek bottle, and 10mL of freshly distilled tetrahydrofuran was added. N-butyllithium (4.4mL, 2.4M n-hexane was added dropwise at -78 ° C) Solution, 10.5 mmol), after about 5 minutes, the solution was returned to room temperature, and the reaction solution was stirred for 2 hours to prepare a lithium dicyclohexylphosphine solution. Another 50mL Shrek bottle was weighed into methyl 2,3-anhydride- 4,6-Oxy-isopropylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve, the solution is added dicyclohexyl through a double needle tip at room temperature Lithium phosphine solution, the reaction solution was stirred and reacted for 6 hours. Under ice-water bath, 0.5 mL of methanol was added, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, the organic phase was washed with saturated ammonium chloride solution, anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 3.3 g of a white solid with a yield of 77%.
31P{ 1H}NMR(162MHz,CDCl 3)δ36.61。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 36.61.
实施例42.(甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-2)-二环己基膦Example 42. (Methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-azandranosidyl-2) -dicyclohexylphosphine
Figure PCTCN2019088461-appb-000061
Figure PCTCN2019088461-appb-000061
在惰性气体保护下中将二环己基膦(2.0mL,10.0mmol)加入50mL史莱克瓶,加入10mL新蒸四氢呋喃.于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,反应液搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃阿洛糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,该溶液在室温下通过双针尖加入二环己基膦锂溶液,反应液搅拌反应6小时.冰水浴下加入0.5mL甲醇,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,有机相用饱和氯化铵溶液洗涤，无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.46g白色固体,产率74％。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) was added to a 50mL Shrek bottle, and 10mL of freshly distilled tetrahydrofuran was added. N-butyllithium (4.4mL, 2.4M n-hexane was added dropwise at -78 ° C) Solution, 10.5 mmol), after about 5 minutes, the solution was returned to room temperature, and the reaction solution was stirred for 2 hours to prepare a lithium dicyclohexylphosphine solution. Another 50mL Shrek bottle was weighed into methyl 2,3-anhydride- 4,6-Oxyl-benzylidene-ɑ-D-pyranoglunoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, the solution is added to the bicyclic ring through the double needle tip at room temperature Lithium hexylphosphine solution, the reaction solution was stirred and reacted for 6 hours. Under ice-water bath, 0.5 mL of methanol was added, the solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, the organic phase was washed with saturated ammonium chloride solution, anhydrous Na 2 SO 4. Dry and remove the solvent under reduced pressure. The residue was recrystallized from methanol to obtain 3.46 g of white solid with a yield of 74%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-2.78。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-2.78.
实施例43.(甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-2)-双(2-联苯基)膦Example 43. (Methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-2) -bis (2-biphenyl) phosphine
Figure PCTCN2019088461-appb-000062
Figure PCTCN2019088461-appb-000062
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,注入2-溴联苯(2.3g,10mmol),于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,搅拌反应1小时.于-78℃下,加入三氯化磷(0.68g,5.0mmol),缓慢回到-40℃再搅拌反应1小时制得双(2-联苯基)氯化膦溶液.剪入金属锂(200mg),搅拌反应24小时.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃阿洛糖苷(2.9g,9.0mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入双(2-联苯基)膦锂溶液,搅拌反应6小时.加入0.5mL甲醇淬灭反应,减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,混合物用硅胶柱层析分离,得到2.6g白色固体,产率86％。Place a 50mL three-necked flask, a spherical condenser, and a constant pressure funnel in a 150 ° C oven to dry overnight and assemble while hot. After pumping and ventilating three times, inject 2-bromobiphenyl (2.3g, 10mmol) at -78 N-Butyllithium (4.4mL, 2.4M n-hexane solution, 10.5mmol) was added dropwise, after 5 minutes of dripping, the reaction was stirred for 1 hour. At -78 ° C, phosphorus trichloride (0.68g, 5.0mmol) was added, Slowly return to -40 ° C and stir for 1 hour to prepare a bis (2-biphenyl) phosphine chloride solution. Cut in lithium metal (200mg) and stir for 24 hours. Take another 50mL Shrek bottle and weigh it into the A 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-pyrano-aluloside (2.9g, 9.0mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve Add lithium bis (2-biphenyl) phosphonate solution to the double needle tip, and stir the reaction for 6 hours. Add 0.5 mL of methanol to quench the reaction, and remove the solvent under reduced pressure. It was separated and purified by silica gel column chromatography, and the mixture was separated by silica gel column chromatography to obtain 2.6 g of white solid with a yield of 86%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-37.97。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-37.97.
实施例44.(R p)-和(S p)-(甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-2)-(3,5-二甲基苯基)-苯基膦 Example 44. (R p )-and (S p )-(methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-azanopyranoside-2)-(3, 5-dimethylphenyl) -phenylphosphine
Figure PCTCN2019088461-appb-000063
Figure PCTCN2019088461-appb-000063
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.用注射器量取3,5-二甲基溴苯(1.36mL,10.0mmol)和10mL无水四氢呋喃入恒压漏斗,通过恒压漏斗先滴加0.5mL的到三口瓶中,搅拌至反应引发后,再往三口瓶中滴加剩余的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回流两小时制得3,5-二甲基苯溴化镁，冷至室温待用.另取一100mL史莱克瓶于惰性气体保护下中量取二氯苯基膦(1.35mL,10.0mmol)溶于10mL的无水四氢呋喃中.于-78℃下,将3,5-二甲基苯基溴化镁格氏试剂通过双针尖滴加至二氯苯基膦溶液中,滴加完毕后,待其回到室温,搅拌反应2小时.另取一100mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水四氢呋喃,用冰水冷至0℃,将苯基-(3,5-二甲基苯基)氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液再氮气下通过硅藻土过滤,再加入无水硫酸钠干燥后,转移至另一已抽换气三次的100mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.5mmol),5分钟滴完,回至室温,搅拌反应2小时.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖将苯基-(3,5-二甲基苯基)膦锂溶液转移至史莱克瓶中,搅拌反应6小时.反应液在冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,无水Nɑ 2SO 4干燥,减压抽除溶剂.产物用硅胶柱层析分离提纯,得到3.6g白色泡沫状固体,产率77％。mp:70.4～73.8℃。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the magnesium scraps with a heated air gun for 15 minutes. After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Use a syringe to measure 3,5-dimethylbromobenzene (1.36mL, 10.0mmol) and 10mL Anhydrous tetrahydrofuran was put into the constant pressure funnel, and 0.5mL was first added dropwise to the three-necked bottle through the constant-pressure funnel, stirred until the reaction was initiated, and then the remaining tetrahydrofuran solution was added dropwise to the three-necked bottle to control the dripping rate so that the reaction solution remained slightly boiling Status. After the dropwise addition, 3,5-dimethylbenzene magnesium bromide was prepared by refluxing at 65 ° C for two hours, and cooled to room temperature for use. Another 100mL Shrek bottle was taken to measure dichlorobenzene under the protection of inert gas. Phosphine (1.35mL, 10.0mmol) was dissolved in 10mL of anhydrous tetrahydrofuran. At -78 ℃, 3,5-dimethylphenyl magnesium bromide Grignard reagent was added dropwise to the dichlorophenyl through a double needle tip In the phosphine solution, after dropping, wait for it to return to room temperature and stir for 2 hours. Take another 100mL Shrek bottle, weigh it into lithium aluminum hydride (370mg, 10.0mmol), and inject 10mL of anhydrous Tetrahydrofuran, cooled to 0 ° C with ice water, the phenyl- (3,5-dimethylphenyl) phosphine chloride solution was added dropwise to the lithium tetrahydrogen aluminum solution through a double needle tip, and the reaction was stirred for 2 hours. Remove the residual lithium aluminum hydride with sodium sulfate, and filter the solution through diatomaceous earth under nitrogen, add anhydrous sodium sulfate to dry, and transfer to another 100mL Shrek bottle that has been ventilated three times. Cool to -78 ℃, add n-butyllithium (4.38mL, 2.4M n-hexane solution, 10.5mmol) dropwise, drop to 5 minutes, return to room temperature, and stir for 2 hours. Take another 50mL Shrek bottle and weigh it into the 2,3-anhydride-4,6-oxo-benzylidene-ɑ-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran and stirring to dissolve, benzene through a double needle tip The lithium- (3,5-dimethylphenyl) phosphine lithium solution was transferred to a Shrek bottle, and the reaction was stirred for 6 hours. The reaction solution was added with 0.5 mL of methanol under an ice water bath, stirred for half an hour, and the solvent was removed under reduced pressure. Dissolve the residue in 15 mL of dichloromethane, and then wash the solution to neutrality with hydrochloric acid (1 M, 15 mL), then wash the organic phase three times with saturated brine (20 mL), dry with anhydrous N 2 SO 4 , and remove the solvent under reduced pressure. The product is separated and extracted by silica gel column chromatography To give a white foamy solid 3.6g, 77% yield. mp: 70.4 ～ 73.8 ℃.
31P{ 1H}NMR(162MHz,CDCl 3)δ-27.16,-31.95。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-27.16, -31.95.
实施例45.(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃阿卓糖苷基-3)-二环己基膦Example 45. (Methyl 3-deoxy-4,6-oxo-benzylidene-β-D-azandranosidyl-3) -dicyclohexylphosphine
Figure PCTCN2019088461-appb-000064
Figure PCTCN2019088461-appb-000064
在惰性气体保护下中量取二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃入50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完,回至室温,搅拌反应2小时,制得二环己基膦锂溶液.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-β-D-甘露吡喃糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,向残余物加入15mL二氯甲烷溶解,再用饱和氯化铵将溶液洗涤,分离出有机相,用无水Nɑ 2SO 4干燥,减压抽除溶剂.混合物用甲醇重结晶,得到3.6g白色固体,产率78％。 Measure dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL freshly distilled tetrahydrofuran into a 50mL Shrek bottle under inert gas protection, and add n-butyllithium (4.4mL, 2.4M n-hexane) dropwise at -78 ℃ Solution, 10.5 mmol), after about 5 minutes of dripping, return to room temperature and stir the reaction for 2 hours to prepare a lithium dicyclohexylphosphine solution. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4, 6-Oxy-benzylidene-β-D-mannopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, adding lithium dicyclohexylphosphine solution through a double needle tip, stirring reaction 6 Add 0.5mL of methanol under ice water bath, stir for half an hour, remove the solvent under reduced pressure, add 15mL of dichloromethane to the residue to dissolve, then wash the solution with saturated ammonium chloride, separate the organic phase, use anhydrous Nɑ 2 SO 4 was dried and the solvent was removed under reduced pressure. The mixture was recrystallized from methanol to obtain 3.6 g of white solid with a yield of 78%.
31P{ 1H}NMR(162MHz,CDCl 3)δ-2.93。 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ-2.93.
实施例46.(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃阿卓糖苷基-3)-二环己基膦-硼烷Example 46. (Methyl 3-deoxy-4,6-oxo-benzylidene-β-D-azandranosidyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000065
Figure PCTCN2019088461-appb-000065
在惰性气体保护下称取(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃阿卓糖苷基-3)-二环己基膦(4.6g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后继续搅拌3小时.减压抽去溶剂,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,经过短硅胶柱提纯,得到4.7g白色泡沫状固体,产率98％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-β-D-pyranazosidyl-3) -dicyclohexylphosphine (4.6g, 10mmol) under inert gas protection, A solution of borane in tetrahydrofuran (1.0 M, 11 mL, 11 mmol) was added dropwise at -20 ° C, and after returning to room temperature, stirring was continued for 3 hours. The solvent was removed under reduced pressure, and 0.5 mL of methanol was added to the residue, followed by 15 mL of dichloromethane Methane was dissolved and purified through a short silica gel column to obtain 4.7g of white foamy solid with a yield of 98%.
31P{ 1H}NMR(162MHz,CDCl 3)δ26.42。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 26.42.
实施例47.(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃阿卓糖苷基-2)-二环己基膦-硼烷Example 47. (Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-β-D-pyran azeptoside-2) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000066
Figure PCTCN2019088461-appb-000066
在惰性气体保护下称取(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃阿卓糖苷基-3)-二环己基膦(4.6g,10mmol),于-20℃下滴加硼烷的四氢呋喃溶液(1.0M,11mL,11mmol),回至室温后继续搅拌3小时.减压抽去溶剂以及多余的硼烷,残余物加入0.5mL的甲醇,再加入15mL的二氯甲烷溶解,得到4.7g白色泡沫状固体,加入NaH(60％的煤油混合物,400mg),搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(1.3mL,20.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到4.7g白色泡沫状固体,产率98％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-β-D-pyranazosidyl-3) -dicyclohexylphosphine (4.6g, 10mmol) under inert gas protection, A solution of borane in tetrahydrofuran (1.0 M, 11 mL, 11 mmol) was added dropwise at -20 ° C, and after returning to room temperature, stirring was continued for 3 hours. The solvent and excess borane were removed under reduced pressure, and 0.5 mL of methanol was added to the residue. Add 15mL of dichloromethane to dissolve to obtain 4.7g of white foamy solid, add NaH (60% kerosene mixture, 400mg), stir for 1 hour, cool to -10 ° C with ice / sodium chloride system, and add iodomethane dropwise (1.3mL, 20.0mmol), the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, the residue was dissolved with 20mL dichloromethane, and then filtered through celite, silica gel column chromatography separation and purification, to obtain 4.7g white foamy solid, The yield is 98%.
1H NMR(400MHz,CDCl 3)δ7.46(dd,J＝6.3,2.7Hz,2H),7.41–7.30(m,3H),5.47(s,1H),4.42(d,J＝6.1Hz,1H),4.32(dd,J＝10.6,4.8Hz,1H),4.00(ddd,J＝10.8,9.4,6.3Hz,1H),3.73(t,J＝10.3Hz,1H),3.66–3.46(m,8H),2.46(dd,J＝19.8,9.0Hz,1H),2.12–1.87(m,5H),1.73(dd,J＝37.7,9.9Hz,5H),1.53–0.83(m,12H),0.41(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J = 6.3, 2.7 Hz, 2H), 7.41–7.30 (m, 3H), 5.47 (s, 1H), 4.42 (d, J = 6.1 Hz, 1H), 4.32 (dd, J = 10.6, 4.8 Hz, 1H), 4.00 (ddd, J = 10.8, 9.4, 6.3 Hz, 1H), 3.73 (t, J = 10.3 Hz, 1H), 3.66-3.46 (m , 8H), 2.46 (dd, J = 19.8, 9.0 Hz, 1H), 2.12–1.87 (m, 5H), 1.73 (dd, J = 37.7, 9.9 Hz, 5H), 1.53–0.83 (m, 12H), 0.41 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.03(s),129.35(s),128.27(s),126.47(s),105.08(d,J＝8.4Hz),102.20(s),77.87(s),76.47(d,J＝3.3Hz),69.36(s),69.01(d,J＝8.6Hz),59.37(s),56.35(s),37.36(s),37.11(s),33.93(s),33.59(d,J＝9.3Hz),33.27(s),28.75(s),28.20(d,J＝2.9Hz),27.90(s),27.76–27.04(m),26.76(d,J＝10.2Hz),26.18(s),25.87(s)。 13 C NMR (101 MHz, CDCl 3 ) δ 137.03 (s), 129.35 (s), 128.27 (s), 126.47 (s), 105.08 (d, J = 8.4 Hz), 102.20 (s), 77.87 (s) , 76.47 (d, J = 3.3 Hz), 69.36 (s), 69.01 (d, J = 8.6 Hz), 59.37 (s), 56.35 (s), 37.36 (s), 37.11 (s), 33.93 (s) , 33.59 (d, J = 9.3 Hz), 33.27 (s), 28.75 (s), 28.20 (d, J = 2.9 Hz), 27.90 (s), 27.76–27.04 (m), 26.76 (d, J = 10.2 Hz), 26.18 (s), 25.87 (s).
31P{ 1H}NMR(162MHz,CDCl 3)δ33.77。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 33.77.
HRMS(ESI)理论值C 27H 44BO 5P+Na +:513.2916.实测值:513.2910。 HRMS (ESI) theoretical value C 27 H 44 BO 5 P + Na + : 513.2916. Found value: 513.2910.
实施例48.(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃艾杜糖苷基-3)-二环己基膦-硼烷Example 48. (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-iduronidinosyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000067
Figure PCTCN2019088461-appb-000067
在惰性气体保护下将二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完.回至室温,搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃塔罗糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入硼烷的二甲硫醚溶液(5mL,2M),搅拌1小时.反应液通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.6g白色固体,产率83％。mp:62.3～64.1℃。 Add dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL freshly distilled tetrahydrofuran to a 50mL Shrek bottle under inert gas protection, and add n-butyllithium (4.4mL, 2.4M n-hexane solution) dropwise at -78 ℃ , 10.5mmol), about 5 minutes after the completion of the drop. Return to room temperature and stir the reaction for 2 hours to prepare a lithium dicyclohexylphosphine solution. Another 50mL Shrek bottle, weighed methyl 2,3-anhydride-4,6 -Oxy-benzylidene-ɑ-D-pyrantaloside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, and adding lithium dicyclohexylphosphine solution through a double needle tip at room temperature, The reaction was stirred for 6 hours. A solution of borane in dimethyl sulfide (5mL, 2M) was added under an ice water bath and stirred for 1 hour. The solvent was removed under reduced pressure, 15mL of dichloromethane was added to dissolve the residue, and then saturated chlorination The ammonium solution was washed, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 3.6 g of white solid with a yield of 83%. mp: 62.3 ～ 64.1 ℃.
1H NMR(400MHz,CDCl 3)δ7.53(m,2H),7.39–7.29(m,3H),5.59(s,1H),5.12(t,J＝4.8Hz,1H),4.38–4.28(m,2H),4.15(dd,J＝12.7,2.0Hz,1H),4.09(t,J＝2.1Hz,1H),3.90(s,1H),3.43(d,J＝0.5Hz,3H),2.28(ddd,J＝11.8,5.4,4.4Hz,1H),2.22–2.09(m,1H),2.08–1.96(m,1H),1.95–1.00(m,19H),0.20(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (m, 2H), 7.39–7.29 (m, 3H), 5.59 (s, 1H), 5.12 (t, J = 4.8 Hz, 1H), 4.38–4.28 ( m, 2H), 4.15 (dd, J = 12.7, 2.0 Hz, 1H), 4.09 (t, J = 2.1 Hz, 1H), 3.90 (s, 1H), 3.43 (d, J = 0.5 Hz, 3H), 2.28 (ddd, J = 11.8, 5.4, 4.4 Hz, 1H), 2.22–2.09 (m, 1H), 2.08–1.96 (m, 1H), 1.95–1.00 (m, 19H), 0.20 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.68,128.79,128.10,125.95,100.15,98.31,76.78,76.74,69.59,68.66,60.63,55.46,38.92,38.67,31.66,31.39,31.37,31.09,28.39,27.64,27.60,27.53,26.97,26.92,26.82,26.76,26.72,26.67,26.64,26.59,25.94,25.85。 13 C NMR (101 MHz, CDCl 3 ) δ 137.68, 128.79, 128.10, 125.95, 100.15, 98.31, 76.78, 76.74, 69.59, 68.66, 60.63, 55.46, 38.92, 38.67, 31.66, 31.39, 31.37, 31.09, 28.39, 27.64, 27.60 , 27.53,26.97,26.92,26.82,26.76,26.72,26.67,26.64,26.59,25.94,25.85.
31P{ 1H}NMR(162MHz,CDCl 3)δ27.41。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 27.41.
实施例49 (甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃艾杜糖苷基-2)-二环己基膦-硼烷Example 49 (methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-iduronidinosyl-2) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000068
Figure PCTCN2019088461-appb-000068
在惰性气体保护下将二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完.回至室温,搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-吡喃古罗糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入硼烷的二甲硫醚溶液(5mL,2M),搅拌1小时.反应液通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到4.0g白色固体,产率84％。 Add dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL freshly distilled tetrahydrofuran to a 50mL Shrek bottle under inert gas protection, and add n-butyllithium (4.4mL, 2.4M n-hexane solution) dropwise at -78 ℃ , 10.5mmol), about 5 minutes after the completion of the drop. Return to room temperature and stir the reaction for 2 hours to prepare a lithium dicyclohexylphosphine solution. Another 50mL Shrek bottle, weighed methyl 2,3-anhydride-4,6 -Oxy-benzylidene-ɑ-D-pyranoglucoside (2.4g, 9.1mmol), evacuate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add lithium dicyclohexylphosphine solution through a double needle tip at room temperature The reaction was stirred for 6 hours. A solution of borane in dimethyl sulfide (5mL, 2M) was added under an ice water bath and stirred for 1 hour. The solvent was removed under reduced pressure, 15mL of dichloromethane was added to dissolve the residue, and then saturated chlorination The ammonium solution was washed, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 4.0 g of white solid with a yield of 84%.
31P{ 1H}NMR(162MHz,CDCl 3)δ26.32。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 26.32.
实施例50.(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃艾杜糖苷基-3)-二环己基膦-硼烷Example 50. (Methyl 3-deoxy-4,6-oxo-benzylidene-β-D-iduronidinosyl-3) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000069
Figure PCTCN2019088461-appb-000069
在惰性气体保护下,将二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完.回至室温,搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-β-D-吡喃古罗糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双 针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入硼烷的二甲硫醚溶液(5mL,2M),搅拌1小时.通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到4.2g白色固体,产率88％。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL freshly distilled tetrahydrofuran were added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane) was added dropwise at -78 ° C Solution, 10.5mmol), about 5 minutes to complete the drop. Return to room temperature and stir for 2 hours to prepare a lithium dicyclohexylphosphonate solution. Another 50mL Shrek bottle, weighed methyl 2,3-anhydride-4, 6-Oxyl-benzylidene-β-D-glucopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, and adding lithium dicyclohexylphosphine solution through a double needle tip at room temperature , Stir the reaction for 6 hours. Add a solution of borane in dimethyl sulfide (5mL, 2M) under an ice-water bath, and stir for 1 hour. Remove the solvent by vacuum, add 15mL of dichloromethane to dissolve the residue, and then use saturated ammonium chloride The solution was washed, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 4.2 g of white solid with a yield of 88%.
31P{ 1H}NMR(162MHz,CDCl 3)δ29.17。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 29.17.
实施例51.(甲基2-脱氧-4,6-氧-苯甲叉基-β-D-吡喃艾杜糖苷基-2)-二环己基膦-硼烷Example 51. (Methyl 2-deoxy-4,6-oxo-benzylidene-β-D-iduronidinosyl-2) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000070
Figure PCTCN2019088461-appb-000070
在惰性气体保护下,将二环己基膦(2.0mL,10.0mmol)和10mL新蒸四氢呋喃加入到50mL史莱克瓶,于-78℃下滴加正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol),约5分钟滴完.回至室温,搅拌反应2小时,制得二环己基膦锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-β-D-吡喃古罗糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入二环己基膦锂溶液,搅拌反应6小时.冰水浴下加入硼烷的二甲硫醚溶液(5mL,2M),搅拌1小时.通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到3.4g白色固体,产率79％。mp:92.2～94.0℃。 Under the protection of inert gas, dicyclohexylphosphine (2.0mL, 10.0mmol) and 10mL freshly distilled tetrahydrofuran were added to a 50mL Shrek bottle, and n-butyllithium (4.4mL, 2.4M n-hexane) was added dropwise at -78 ° C Solution, 10.5mmol), about 5 minutes to complete the drop. Return to room temperature and stir for 2 hours to prepare a lithium dicyclohexylphosphonate solution. Another 50mL Shrek bottle, weighed methyl 2,3-anhydride-4, 6-Oxyl-benzylidene-β-D-glucopyranoside (2.4g, 9.1mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, and adding lithium dicyclohexylphosphine solution through a double needle tip at room temperature , Stir the reaction for 6 hours. Add a solution of borane in dimethyl sulfide (5mL, 2M) under an ice-water bath, and stir for 1 hour. Remove the solvent by vacuum, add 15mL of dichloromethane to dissolve the residue, and then use saturated ammonium chloride The solution was washed, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 3.4 g of white solid with a yield of 79%. mp: 92.2 ～ 94.0 ℃.
1H NMR(400MHz,CDCl 3)δ7.55–7.48(m,2H),7.32(m,3H),5.54(s,1H),5.01(dd,J＝10.1,2.6Hz,1H),4.60(dd,J＝7.7,5.3Hz,1H),4.31(d,J＝12.6Hz,1H),4.08(dd,J＝12.6,2.1Hz,1H),3.97(d,J＝1.7Hz,1H),3.77(d,J＝2.2Hz,1H),3.45(s,3H),2.47(qt,J＝12.8,2.9Hz,1H),2.30(ddd,J＝10.3,5.3,2.6Hz,1H),2.25–2.06(m,2H),1.95–0.94(m,18H),0.87(q,J＝5.2,4.1Hz,1H),0.34(dtd,J＝16.2,12.5,12.0,5.7Hz,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.55–7.48 (m, 2H), 7.32 (m, 3H), 5.54 (s, 1H), 5.01 (dd, J = 10.1, 2.6 Hz, 1H), 4.60 ( dd, J = 7.7, 5.3 Hz, 1H), 4.31 (d, J = 12.6 Hz, 1H), 4.08 (dd, J = 12.6, 2.1 Hz, 1H), 3.97 (d, J = 1.7 Hz, 1H), 3.77 (d, J = 2.2 Hz, 1H), 3.45 (s, 3H), 2.47 (qt, J = 12.8, 2.9 Hz, 1H), 2.30 (ddd, J = 10.3, 5.3, 2.6 Hz, 1H), 2.25 -2.06 (m, 2H), 1.95-0.94 (m, 18H), 0.87 (q, J = 5.2, 4.1 Hz, 1H), 0.34 (dtd, J = 16.2, 12.5, 12.0, 5.7 Hz, 4H).
13C NMR(101MHz,CDCl 3)δ137.96,128.69,128.09,125.99,100.47,100.00,99.94,77.29,77.24,70.09,68.82,68.77,66.19,55.28,39.24,39.00,34.68,31.59,31.54, 31.22,30.64,30.35,28.94,28.09,27.20,27.17,27.13,27.11,26.97,26.86,26.85,26.72,26.43,26.29,26.06,26.01,25.30,22.66,20.73,14.20,14.15。 13 C NMR (101 MHz, CDCl 3 ) δ 137.96, 128.69, 128.09, 125.99, 100.47, 100.00, 99.94, 77.29, 77.24, 70.09, 68.82, 68.77, 66.19, 55.28, 39.24, 39.00, 34.68, 31.59, 31.54, 31.22, 30.64 , 30.35,28.94,28.09,27.20,27.17,27.13,27.11,26.97,26.86,26.85,26.72,26.43,26.29,26.06,26.01,25.30,22.66,20.73,14.20,14.15.
31P{ 1H}NMR(162MHz,CDCl 3)δ27.52。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 27.52.
实施例52.(甲基3-氧-甲基-2-脱氧-4,6-氧-苯甲叉基-β-D-吡喃艾杜糖苷基-2)-二环己基膦-硼烷Example 52. (Methyl 3-oxo-methyl-2-deoxy-4,6-oxo-benzylidene-β-D-iduronidinosyl-2) -dicyclohexylphosphine-borane
Figure PCTCN2019088461-appb-000071
Figure PCTCN2019088461-appb-000071
称取(甲基3-脱氧-4,6-氧-苯甲叉基-β-D-吡喃艾杜糖苷基-3)-二环己基膦-硼烷(1.0g,2.1mmol)置于50mL史莱克瓶中,抽换气三次,注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,80mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.13mL,2.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.0g白色固体,产率93％。Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-β-D-iduronidinosyl-3) -dicyclohexylphosphine-borane (1.0g, 2.1mmol) in In a 50mL Shrek bottle, ventilate three times, inject 10mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NaH (60% kerosene mixture, 80mg) under an inert gas atmosphere, stir for 1 hour, use ice / The sodium chloride system was cooled to -10 ° C, iodomethane (0.13 mL, 2.0 mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20 mL of dichloromethane, then filtered through celite, silica gel Separation and purification by column chromatography gave 1.0 g of white solid with a yield of 93%.
1H NMR(400MHz,CDCl 3)δ7.57(m,2H),7.37–7.27(m,3H),5.59(s,1H),4.90(dd,J＝14.4,3.0Hz,1H),4.36(dd,J＝12.6,1.2Hz,1H),4.29(dt,J＝5.6,2.5Hz,1H),4.11(dd,J＝12.6,2.2Hz,1H),3.95(t,J＝1.8Hz,1H),3.64(q,J＝1.8Hz,1H),3.47(s,3H),3.44(s,3H),2.70–2.55(m,1H),2.45–2.27(m,3H),1.90–0.78(m,19H),0.12(br,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.57 (m, 2H), 7.37–7.27 (m, 3H), 5.59 (s, 1H), 4.90 (dd, J = 14.4, 3.0 Hz, 1H), 4.36 ( dd, J = 12.6, 1.2 Hz, 1H), 4.29 (dt, J = 5.6, 2.5 Hz, 1H), 4.11 (dd, J = 12.6, 2.2 Hz, 1H), 3.95 (t, J = 1.8 Hz, 1H) ), 3.64 (q, J = 1.8 Hz, 1H), 3.47 (s, 3H), 3.44 (s, 3H), 2.70–2.55 (m, 1H), 2.45–2.27 (m, 3H), 1.90–0.78 ( m, 19H), 0.12 (br, 3H).
13C NMR(101MHz,CDCl 3)δ137.83,128.54,128.02,125.81,101.97,101.92,100.08,78.52,78.47,73.53,69.87,67.54,56.99,55.88,35.10,34.87,31.60,31.28,30.38,30.10,29.24,29.23,28.44,27.37,27.32,27.27,27.16,27.06,26.91,26.86,26.82,26.74,26.11,26.04,26.00,25.90。 13 C NMR (101 MHz, CDCl 3 ) δ 137.83, 128.54, 128.02, 125.81, 101.97, 101.92, 100.08, 78.52, 78.47, 73.53, 69.87, 67.54, 56.99, 55.88, 35.10, 34.87, 31.60, 31.28, 30.38, 30.10, 29.24 , 29.23, 28.44, 27.37, 27.32, 27.27, 27.16, 27.06, 26.91, 26.86, 26.82, 26.74, 26.11, 26.04, 26.00, 25.90.
31P{ 1H}NMR(162MHz,CDCl 3)δ31.63。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 31.63.
实施例53. 4-甲氧基-9-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-9-磷杂芴Example 53. 4-Methoxy-9- (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -9-phosphafluorene
Figure PCTCN2019088461-appb-000072
Figure PCTCN2019088461-appb-000072
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,在氮气下加入4-甲氧基-9-磷杂芴(2.14g,10.0mmol),注入30mL无水四氢呋喃,用液氮/丙酮体系冷却至-78℃,滴入正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol)。回至室温,搅拌反应2小时,制得4-甲氧基-9-磷杂芴锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-α-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入4-甲氧基-9-磷杂芴锂溶液,搅拌反应6小时.通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到4.4g白色固体混合物,产率92％。 Place a 50mL three-necked bottle, a spherical condenser, and a constant pressure funnel in a 150 ° C oven to dry overnight, and assemble while hot. After ventilating three times, add 4-methoxy-9-phosphafluorene (2.14g) under nitrogen , 10.0mmol), inject 30mL of anhydrous tetrahydrofuran, cooled to -78 ℃ with liquid nitrogen / acetone system, dripped n-butyllithium (4.4mL, 2.4M n-hexane solution, 10.5mmol). Return to room temperature and stir the reaction for 2 hours to prepare a lithium 4-methoxy-9-phosphafluorene solution. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzene Methylene-α-D-mannopyranoside (2.4g, 9.1mmol), ventilate three times, inject 10mL of tetrahydrofuran and stir to dissolve, add 4-methoxy-9-phosphafluorene lithium through a double needle tip at room temperature The solution was stirred and reacted for 6 hours. The solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and then washed with saturated ammonium chloride solution, dried over anhydrous Na 2 SO 4 , the solvent was removed under reduced pressure. The residue was extracted with methanol Recrystallization gave 4.4g of a white solid mixture with a yield of 92%.
1H NMR(400MHz,CDCl 3)δ8.51(dd,J＝41.4,7.9Hz,1H),7.69–7.56(m,3H),7.50–7.33(m,5H),7.29(q,J＝7.1,6.7Hz,2H),6.97(d,J＝8.1Hz,1H),6.85(dd,J＝6.3,2.3Hz,2H),5.66(s,1H),4.82–4.67(m,2H),4.50–4.38(m,2H),4.10(dd,J＝8.1,3.7Hz,1H),3.97(d,J＝12.0Hz,3H),3.87(td,J＝10.4,2.1Hz,1H),3.61(s,3H),2.35–2.23(m,1H),0.88(qt,J＝6.0,2.7Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (dd, J = 41.4, 7.9 Hz, 1H), 7.69–7.56 (m, 3H), 7.50–7.33 (m, 5H), 7.29 (q, J = 7.1 , 6.7Hz, 2H), 6.97 (d, J = 8.1Hz, 1H), 6.85 (dd, J = 6.3, 2.3Hz, 2H), 5.66 (s, 1H), 4.82-4.67 (m, 2H), 4.50 – 4.38 (m, 2H), 4.10 (dd, J = 8.1, 3.7 Hz, 1H), 3.97 (d, J = 12.0 Hz, 3H), 3.87 (td, J = 10.4, 2.1 Hz, 1H), 3.61 ( s, 3H), 2.35-2.23 (m, 1H), 0.88 (qt, J = 6.0, 2.7 Hz, 1H).
13C NMR(101MHz,CDCl 3)δ183.60,157.30,156.74,146.58,146.50,144.58,143.68,143.61,142.81,142.20,142.11,139.26,139.17,137.39,137.36,132.81,132.80,132.72,132.62,132.51,132.40,131.05,131.03,129.28,129.26,128.58,128.28,128.28,128.04,127.38,127.30,127.26,127.18,126.79,126.39,125.76,125.73,125.70,125.66,125.63,125.40,125.32,125.18,125.10,110.94,110.50,102.61,100.77,100.73,77.38,77.30,77.26,77.20,71.05,71.01,70.87,70.83,69.27,61.20,61.18,61.09,61.07,55.38,55.35,54.83,54.82,44.12,43.93,43.83,43.63. 13 C NMR (101 MHz, CDCl 3 ) δ 183.60, 157.30, 156.74, 146.58, 146.50, 144.58, 143.68, 143.61, 142.81, 142.20, 142.11, 139.26, 139.17, 137.39, 137.36, 132.81, 132.80, 132.72, 132.51, 132.40 , 131.05,131.03,129.28,129.26,128.58,128.28,128.28,128.04,127.38,127.30,127.26,127.18,126.79,126.39,125.76,125.73,125.70,125.66,125.63,125.40,125.32,125.18,125.10,110.94,110.94 , 102.61,100.77,100.73,77.38,77.30,77.26,77.20,71.05,71.01,70.87,70.83,69.27,61.20,61.18,61.09,61.07,55.38,55.35,54.83,54.82,44.12,43.93,43.83,43.63.
31P NMR(162MHz,CDCl 3)δ-16.45,-16.52。 31 P NMR (162 MHz, CDCl 3 ) δ-16.45, -16.52.
实施例54. 9-(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-9-磷杂芴Example 54. 9- (Methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -9-phosphafluorene
Figure PCTCN2019088461-appb-000073
Figure PCTCN2019088461-appb-000073
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,在氮气下加入9-磷杂芴(1.84g,10.0mmol),注入30mL无水四氢呋喃,用液氮/丙酮体系冷却至-78℃,滴入正丁基锂(4.4mL,2.4M的正己烷溶液,10.5mmol).回至室温,搅拌反应2小时,制得9-磷杂芴锂溶液.另取一个50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-α-D-吡喃甘露糖苷(2.4g,9.1mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,在室温下通过双针尖加入9-磷杂芴锂溶液,搅拌反应6小时。通过减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用饱和氯化铵溶液洗涤,无水Na 2SO 4干燥,减压抽除溶剂.残余物用甲醇重结晶,得到4.2g白色固体,产率87％。 Place a 50mL three-necked bottle, a spherical condenser, and a constant pressure funnel in a 150 ° C oven to dry overnight, and assemble while hot. After pumping and ventilating three times, add 9-phosphafluorene (1.84g, 10.0mmol) under nitrogen and inject 30mL of anhydrous tetrahydrofuran, cooled to -78 ° C with a liquid nitrogen / acetone system, and dripped n-butyllithium (4.4mL, 2.4M in n-hexane solution, 10.5mmol). Return to room temperature and stir for 2 hours to prepare 9 -Lithium phosphafluorene solution. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene-α-D-mannopyranoside (2.4g, 9.1mmol) ), Pumping and ventilating three times, injecting 10 mL of tetrahydrofuran with stirring and dissolving, adding 9-phosphafluorene lithium solution through a double needle tip at room temperature, and stirring to react for 6 hours. The solvent was removed under reduced pressure, 15 mL of dichloromethane was added to dissolve the residue, and then washed with saturated ammonium chloride solution, dried over anhydrous Na 2 SO 4 , the solvent was removed under reduced pressure. The residue was recrystallized from methanol to obtain 4.2 g of white Solid, yield 87%.
31P{ 1H}NMR(162MHz,CDCl 3)δ17.82。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 17.82.
实施例55.(R p)-{(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-[2,6-双(2-甲基苯基)苯基-1-]膦}-(N,N-二甲基苯甲胺基-2-η 2-C,N)-氯化钯(II) Example 55. (R p )-{(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3)-[ 2,6-bis (2-methylphenyl) phenyl-1-] phosphine)-(N, N-dimethylbenzylamino-2-η 2 -C, N) -palladium chloride (II )
Figure PCTCN2019088461-appb-000074
Figure PCTCN2019088461-appb-000074
将50mL三口瓶,球形冷凝管,恒压漏斗置于150℃烘箱中烘干过夜,趁热组装.抽换气三次后,称入剪碎的镁屑(260mg,11.0mmol)于三口瓶中,抽至真空状态,用加热风枪加热活化镁屑15分钟,待三口瓶冷却至室温后,充回氮气.量取2-溴甲苯(3.4g,20.0mmol)入恒压漏斗,再注入10mL无水四氢呋喃.通过恒压漏斗先滴加0.5mL的进三口瓶中,搅拌至反应引发后,再往三口瓶中滴加的四氢呋喃溶液,控制滴加速度使得反应液保持微沸状态.滴加完毕后,65℃回 流两小时.于惰性气体保护下中量取间二氯苯(1.47g,10.0mmol),注入10mL的无水四氢呋喃,于-78℃下,滴加正丁基锂(2.5M,4.0mL,10.0mmol)反应2小时.于-78℃下,将2-甲苯溴化镁格氏试剂通过双针尖滴加至间二氯苯的正丁基锂溶液中,滴加完毕后,于70℃,搅拌反应2小时制得2,6-双(2-甲基苯基)-1-苯基溴(氯)化镁格氏试剂.于惰性气体保护下中量取三氯化磷(0.67g,10.0mmol),注入10mL的无水四氢呋喃.于-78℃下,将上面制备的格氏试剂通过双针尖滴加至三氯化磷溶液中,滴加完毕后,待其回到-40℃,搅拌反应2小时.另取一个50mL史莱克瓶,称入四氢锂铝(370mg,10.0mmol),注入10mL的无水乙醚,用冰水冷至0℃,将2,6-双(2-甲基苯基)-1-苯基二氯化膦溶液通过双针尖滴加至四氢锂铝溶液中,搅拌反应2小时.用5g的十水硫酸钠除去残余的四氢锂铝,溶液在氮气下通过硅藻土过滤,再加入无水硫酸钠干燥后,转移至另一已抽换气三次的50mL的史莱克瓶.冷至-78℃,向其滴加正丁基锂(4.38mL,2.4M的正己烷溶液,10.6mmol),约5分钟滴完,回至室温,搅拌反应1小时.另取一50mL史莱克瓶,称入甲基2,3-酐-4,6-氧-苯甲叉基-ɑ-D-甘露吡喃糖苷(1.2g,4.5mmol),抽换气三次,注入10mL四氢呋喃搅拌溶解,通过双针尖加入上面制备的2,6-双(2-甲基苯基)-(1-苯基)膦锂溶液,搅拌反应15小时.冰水浴下加入0.5mL甲醇,搅拌半小时,减压抽去溶剂,加入15mL二氯甲烷溶解残余物,再用盐酸(1M,15mL)将溶液洗涤至中性,接着用饱和食盐水(20mL)洗涤有机相三次,用无水Na 2SO 4干燥,得到粗产品.注入10mL无水四氢呋喃,冰水浴将混合物冷却至0℃,于惰性气体保护下加入NaH(60％的煤油混合物,400mg)搅拌1小时后,用冰/氯化钠体系冷却至-10℃,滴加碘甲烷(0.13mL,5.0mmol),搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到1.7为白色固体的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-[2,6-双(2-甲基苯基)-1-苯基]膦,产率31％。 Place a 50mL three-necked bottle, a spherical condenser, and a constant-pressure funnel in a 150 ° C oven to dry overnight, assemble while hot. After pumping and ventilating three times, weigh in the shredded magnesium shavings (260mg, 11.0mmol) in the three-necked bottle. Evacuate to a vacuum state and heat the activated magnesium scraps with a heated air gun for 15 minutes.After the three-necked bottle is cooled to room temperature, fill it with nitrogen. Take 2-bromotoluene (3.4g, 20.0mmol) into a constant pressure funnel and inject 10mL without Water tetrahydrofuran. Add 0.5mL into the three-necked bottle through a constant pressure funnel, stir until the reaction is initiated, and then add the tetrahydrofuran solution to the three-necked bottle to control the dripping rate so that the reaction solution remains slightly boiling. , Reflux at 65 ℃ for two hours. Take m-dichlorobenzene (1.47g, 10.0mmol) under the protection of inert gas, inject 10mL of anhydrous tetrahydrofuran, and drop n-butyllithium (2.5M, 4.0mL, 10.0mmol) for 2 hours. At -78 ° C, 2-toluene magnesium bromide Grignard reagent was added dropwise to the n-butyllithium solution of m-dichlorobenzene through a double needle tip. Stir the reaction at 70 ° C for 2 hours to prepare 2,6-bis (2-methylphenyl) -1-phenylmagnesium bromide (Cl) reagent Grignard reagent. Measure phosphorus trichloride under the protection of inert gas ( 0.67g, 10.0mmol), Note 10mL of anhydrous tetrahydrofuran was added. At -78 ℃, the Grignard reagent prepared above was added dropwise to the phosphorus trichloride solution through a double needle tip. After the addition was completed, wait for it to return to -40 ℃ and stir the reaction for 2 hours Take another 50mL Shrek bottle, weigh it into lithium aluminum hydride (370mg, 10.0mmol), inject 10mL of anhydrous ether, cool to 0 ° C with ice water, and transfer 2,6-bis (2-methylphenyl) The -1-phenylphosphine dichloride solution was added dropwise to the lithium aluminum hydride solution through a double needle tip, and the reaction was stirred for 2 hours. The residual lithium aluminum hydride was removed with 5 g of sodium sulfate decahydrate, and the solution was passed through diatom under nitrogen After filtration, add anhydrous sodium sulfate to dry, transfer to another 50mL Shrek bottle that has been pumped and ventilated three times. Cool to -78 ° C, and add n-butyl lithium (4.38mL, 2.4M n-hex) to it dropwise Alkane solution, 10.6 mmol), after about 5 minutes of dripping, return to room temperature and stir the reaction for 1 hour. Take another 50mL Shrek bottle and weigh in methyl 2,3-anhydride-4,6-oxo-benzylidene -ɑ-D-mannopyranoside (1.2g, 4.5mmol), pumping and ventilating three times, injecting 10mL of tetrahydrofuran to stir and dissolve, add 2,6-bis (2-methylphenyl)-(prepared above) through the double needle tip 1-Phenyl) phosphine lithium solution, stirring and reacting for 15 hours. Add 0.5mL methanol under ice water bath , Stir for half an hour, remove the solvent under reduced pressure, add 15mL of dichloromethane to dissolve the residue, then wash the solution with hydrochloric acid (1M, 15mL) to neutral, then wash the organic phase three times with saturated brine (20mL), using Dry with water Na 2 SO 4 to obtain crude product. Inject 10 mL of anhydrous tetrahydrofuran, cool the mixture to 0 ° C in an ice water bath, add NaH (60% kerosene mixture, 400 mg) under an inert gas atmosphere, stir for 1 hour, use ice / The sodium chloride system was cooled to -10 ° C, iodomethane (0.13mL, 5.0mmol) was added dropwise, and the reaction was stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved with 20mL of dichloromethane, then filtered through celite, silica gel Separation and purification by column chromatography to obtain 1.7 as a white solid (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -[2,6-bis (2-methylphenyl) -1-phenyl] phosphine, yield 31%.
称取568.0mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-[2,6-双(2-甲基苯基)-1-苯基]膦加入268.5mg的二聚[(N,N-二甲基苯甲胺基-2-η 2-C,N)PdCl(II)],抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应6小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到0.7g黄色固体,产率83％。 Weigh out 568.0mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3)-(2,6-bis (2-methylphenyl) -1-phenyl] phosphine added 268.5mg of dimerized [(N, N-dimethylbenzylamino-2-η 2 -C, N) PdCl (II)], Pumping and ventilating three times, injecting 10 mL of degassed anhydrous dichloromethane and stirring to react for 6 hours. The solvent was removed under reduced pressure, the residue was dissolved with 20 mL of dichloromethane, and then filtered through celite, and purified by silica gel column chromatography , 0.7g yellow solid was obtained with a yield of 83%.
1H NMR(400MHz,CDCl 3)δ7.63(dt,J＝7.4,3.9Hz,1H),7.44(d,J＝7.4Hz,1H),7.34–7.27(m,2H),7.25–7.02(m,8H),7.00–6.84(m,4H),6.84–6.74(m,4H),6.58–6.44(m,2H),6.25(dd,J＝17.5,9.5Hz,1H),5.63(d,J＝11.7Hz,1H),5.48(t,J＝8.7Hz,1H),4.61(d,J＝6.6Hz,1H),4.52–4.36(m,4H),4.27(td,J＝9.9,5.1Hz,1H),4.03–3.89(m,2H),3.36(s,3H),3.22(dd,J＝11.3,4.8Hz,1H),3.19(d,J＝5.7Hz,3H),2.83(t,J＝3.6Hz,3H),2.50(s,3H),2.30(s,3H),1.66(s,1H),1.18(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (dt, J = 7.4, 3.9 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.34–7.27 (m, 2H), 7.25–7.02 ( m, 8H), 7.00–6.84 (m, 4H), 6.84–6.74 (m, 4H), 6.58–6.44 (m, 2H), 6.25 (dd, J = 17.5, 9.5 Hz, 1H), 5.63 (d, J = 11.7 Hz, 1H), 5.48 (t, J = 8.7 Hz, 1H), 4.61 (d, J = 6.6 Hz, 1H), 4.52–4.36 (m, 4H), 4.27 (td, J = 9.9, 5.1 Hz, 1H), 4.03-3.89 (m, 2H), 3.36 (s, 3H), 3.22 (dd, J = 11.3, 4.8 Hz, 1H), 3.19 (d, J = 5.7 Hz, 3H), 2.83 (t , J = 3.6 Hz, 3H), 2.50 (s, 3H), 2.30 (s, 3H), 1.66 (s, 1H), 1.18 (s, 3H).
13C NMR(101MHz,CDCl 3)δ149.25,148.04,146.77,144.34,141.77,141.04,137.93,137.41,136.95,134.61,134.44,132.08,131.84,131.75,131.65,130.40,129.88,129.39,128.52,128.28,128.11,127.83,127.08,126.82,126.76,125.94,125.71,124.54,124.33,123.56,122.62,102.02,99.82,78.31,78.16,77.12,73.45,73.42,69.71,59.56,57.45,54.66,51.23,48.06,34.23,34.06,22.75,19.36. 13 C NMR (101 MHz, CDCl 3 ) δ 149.25, 148.04, 146.77, 144.34, 141.77, 141.04, 137.93, 137.41, 136.95, 134.61, 134.44, 132.08, 131.84, 131.75, 131.65, 130.40, 129.88, 129.39, 128.52, 128.28, 128.11 , 127.83,127.08,126.82,126.76,125.94,125.71,124.54,124.33,123.56,122.62,102.02,99.82,78.31,78.16,77.12,73.45,73.42,69.71,59.56,57.45,54.66,51.23,48.06,34.23,34.23 , 22.75, 19.36.
31P{ 1H}NMR(162MHz,CDCl 3)δ-7.26。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ-7.26.
实施例56.(R p)-{(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-[(2-联苯基)]膦}-(N,N-二甲基苯甲胺基-2-η 2-C,N)-氯化钯(II) Example 56. (R p )-{(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3)-[ (2-Biphenyl)) phosphine)-(N, N-dimethylbenzylamino-2-η 2 -C, N) -palladium (II) chloride
Figure PCTCN2019088461-appb-000075
Figure PCTCN2019088461-appb-000075
称取463.0mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-(2-联苯基)膦与268.5mg的二聚苄胺钯,抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应2小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.7g黄色固体,产率95％。Weigh 463.0mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3)-(2-biphenyl ) Phosphine and 268.5 mg of dimerized benzylamine palladium, pumping and ventilating three times, injecting 10 mL of degassed anhydrous dichloromethane, stirring and reacting for 2 hours. Filtration through celite, separation and purification by silica gel column chromatography, 0.7 g Yellow solid, yield 95%.
1H NMR(400MHz,CDCl 3)δ8.46(s,1H),8.06(t,J＝7.7Hz,1H),7.84(dd,J＝23.8,7.6Hz,2H),7.47(ddt,J＝29.7,10.5,7.4Hz,5H),7.32(t,J＝7.3Hz,1H),7.21(q,J＝7.8Hz,3H),6.82(d,J＝7.2Hz,1H),6.72(t,J＝7.3Hz,1H),6.22(t,J＝7.5Hz,1H),5.70(s,1H),5.51(t,J＝7.5Hz,1H),5.28(s,1H),5.00(s,1H),4.67–4.47 (m,1H),4.28(s,1H),4.11(dd,J＝9.8,4.2Hz,1H),3.83–3.62(m,3H),3.24(s,4H),2.83(d,J＝14.8Hz,3H),2.74–2.38(m,6H),1.70(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.06 (t, J = 7.7 Hz, 1H), 7.84 (dd, J = 23.8, 7.6 Hz, 2H), 7.47 (ddt, J = 29.7, 10.5, 7.4Hz, 5H), 7.32 (t, J = 7.3Hz, 1H), 7.21 (q, J = 7.8Hz, 3H), 6.82 (d, J = 7.2Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 6.22 (t, J = 7.5 Hz, 1H), 5.70 (s, 1H), 5.51 (t, J = 7.5 Hz, 1H), 5.28 (s, 1H), 5.00 (s, 1H), 4.67–4.47 (m, 1H), 4.28 (s, 1H), 4.11 (dd, J = 9.8, 4.2 Hz, 1H), 3.83–3.62 (m, 3H), 3.24 (s, 4H), 2.83 (d, J = 14.8 Hz, 3H), 2.74-2.38 (m, 6H), 1.70 (s, 1H).
13C NMR(101MHz,CDCl 3)δ150.75,148.34,148.32,145.26,143.44,137.64,136.50,136.38,133.78,133.65,133.38,133.25,133.18,131.00,130.97,128.90,128.30,128.15,127.82,127.71,126.50,124.94,124.89,123.64,121.94,121.16,121.10,120.62,120.56,102.69,100.05,78.27,76.82,72.73,72.70,69.83,60.81,58.13,54.00,53.46,51.18,49.32,40.24,40.02。 13 C NMR (101 MHz, CDCl 3 ) δ 150.75, 148.34, 148.32, 145.26, 143.44, 137.64, 136.50, 136.38, 133.78, 133.65, 133.38, 133.25, 133.18, 131.00, 130.97, 128.90, 128.30, 128.15, 127.82, 127.71, 126.50 , 124.94,124.89,123.64,121.94,121.16,121.10,120.62,120.56,102.69,100.05,78.27,76.82,72.73,72.70,69.83,60.81,58.13,54.00,53.46,51.18,49.32,40.24,40.02.
31P{ 1H}NMR(162MHz,CDCl 3)δ22.66。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 22.66.
实施例57.[(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(N,N-二甲基苯甲胺-2-η 2-C,N)-氯化钯(II) Example 57. [(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]-(N, N-dimethyl Benzylamine-2-η 2 -C, N) -palladium (II) chloride
Figure PCTCN2019088461-appb-000076
Figure PCTCN2019088461-appb-000076
称取(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦462mg与268.5mg的二聚[(N,N-二甲基苯甲胺基-2-η 2-C,N)-PdCl(II)],抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到0.71g黄色固体,产率96％。mp:129.8～131.6℃。 Weigh (methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine 462mg and 268.5mg dimerization ((N, N -Dimethylbenzylamino-2-η 2 -C, N) -PdCl (II)], pumping and ventilating three times, injecting 10 mL of degassed anhydrous dichloromethane, and stirring to react for 1 hour. The solvent was removed, and the residue was dissolved in 20 mL of dichloromethane, filtered through celite, and purified by silica gel column chromatography to obtain 0.71 g of yellow solid with a yield of 96%. mp: 129.8 ～ 131.6 ℃.
1H NMR(400MHz,CDCl 3)δ7.50(dt,J＝6.6,3.6Hz,2H),7.39–7.33(m,3H),7.02–6.93(m,2H),6.89(t,J＝7.3Hz,1H),6.56(t,J＝7.5Hz,1H),5.61(s,1H),4.88(s,1H),4.51(d,J＝12.7Hz,1H),4.23(ddd,J＝9.9,4.2,1.4Hz,1H),4.12(d,J＝5.9Hz,1H),3.91(t,J＝10.2Hz,1H),3.86–3.74(m,1H),3.44(s,3H),3.00(td,J＝11.4,1.9Hz,1H),2.79(d,J＝2.6Hz,3H),2.73–2.66(m,3H),2.40(q,J＝12.0,11.5Hz,2H),2.14(d,J＝12.8Hz,1H),1.99–1.18(m,18H),0.77–0.58(m,2H),0.51(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (dt, J = 6.6, 3.6 Hz, 2H), 7.39–7.33 (m, 3H), 7.02–6.93 (m, 2H), 6.89 (t, J = 7.3 Hz, 1H), 6.56 (t, J = 7.5Hz, 1H), 5.61 (s, 1H), 4.88 (s, 1H), 4.51 (d, J = 12.7Hz, 1H), 4.23 (ddd, J = 9.9 , 4.2, 1.4Hz, 1H), 4.12 (d, J = 5.9Hz, 1H), 3.91 (t, J = 10.2Hz, 1H), 3.86-3.74 (m, 1H), 3.44 (s, 3H), 3.00 (td, J = 11.4, 1.9 Hz, 1H), 2.79 (d, J = 2.6 Hz, 3H), 2.73–2.66 (m, 3H), 2.40 (q, J = 12.0, 11.5 Hz, 2H), 2.14 ( d, J = 12.8 Hz, 1H), 1.99–1.18 (m, 18H), 0.77–0.58 (m, 2H), 0.51 (s, 1H).
13C NMR(101MHz,CDCl 3)δ147.99,137.25,136.41,136.33,129.49,128.32,126.66,125.66,125.62,124.32,123.07,102.80,99.94,76.74,76.66,72.40,69.41, 65.80,55.07,50.49,49.42,35.52,35.30,31.78,31.40,30.75,29.24,28.10,28.00,27.76,27.65,27.38,27.24,27.18,27.08,26.41,25.70。 13 C NMR (101 MHz, CDCl 3 ) δ 147.99, 137.25, 136.41, 136.33, 129.49, 128.32, 126.66, 125.66, 125.62, 124.32, 123.07, 102.80, 99.94, 76.74, 76.66, 72.40, 69.41, 65.80, 55.07, 50.49, 49.42 , 35.52,35.30,31.78,31.40,30.75,29.24,28.10,28.00,27.76,27.65,27.38,27.24,27.18,27.08,26.41,25.70.
31P{ 1H}NMR(162MHz,CDCl 3)δ41.99。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 41.99.
实施例58.[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(N,N-二甲基苯甲胺-2-η 2-C,N)-氯化钯(II) Example 58. [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]- (N, N-dimethylbenzylamine-2-η 2 -C, N) -palladium (II) chloride
Figure PCTCN2019088461-appb-000077
Figure PCTCN2019088461-appb-000077
称取(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦476mg与268.5mg的二聚[(N,N-二甲基苯甲胺基-2-η 2-C,N)-PdCl(II)],抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.减压抽除溶剂,残余物用20mL二氯甲烷溶解,再经硅藻土过滤,硅胶柱层析分离提纯,得到0.7g黄色固体,产率93％。 Weigh (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine 476mg and 268.5mg Dimerize [(N, N-dimethylbenzylamino-2-η 2 -C, N) -PdCl (II)], pump and ventilate three times, inject 10 mL of degassed anhydrous dichloromethane, and stir The reaction was conducted for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane, filtered through celite, and purified by silica gel column chromatography to obtain 0.7 g of a yellow solid with a yield of 93%.
1H NMR(400MHz,CDCl 3)δ7.51(s,3H),7.38–7.28(m,3H),6.92(q,J＝7.3,5.8Hz,2H),6.87–6.78(m,1H),5.51(s,1H),4.71(s,1H),4.41(dd,J＝15.3,7.5Hz,1H),4.32(dd,J＝10.4,5.0Hz,1H),4.23(s,1H),3.73(t,J＝10.1Hz,1H),3.69–3.62(m,1H),3.59(s,2H),3.53–3.33(m,4H),2.87–2.54(m,4H),2.40(d,J＝10.7Hz,2H),2.31–1.80(m,5H),1.79–1.36(m,9H),1.30–0.77(m,8H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 3H), 7.38–7.28 (m, 3H), 6.92 (q, J = 7.3, 5.8 Hz, 2H), 6.87–6.78 (m, 1H), 5.51 (s, 1H), 4.71 (s, 1H), 4.41 (dd, J = 15.3, 7.5Hz, 1H), 4.32 (dd, J = 10.4, 5.0Hz, 1H), 4.23 (s, 1H), 3.73 (t, J = 10.1 Hz, 1H), 3.69–3.62 (m, 1H), 3.59 (s, 2H), 3.53–3.33 (m, 4H), 2.87–2.54 (m, 4H), 2.40 (d, J = 10.7 Hz, 2H), 2.31–1.80 (m, 5H), 1.79–1.36 (m, 9H), 1.30–0.77 (m, 8H).
13C NMR(101MHz,CDCl 3)δ151.55,147.96,137.39,136.72,136.65,128.98,128.13,126.59,125.10,125.05,123.61,122.42,102.96,99.95,81.42,77.64,77.59,73.01,70.08,60.92,58.91,54.31,50.93,37.26,35.48,32.48,30.97,30.92,29.94,29.71,28.08,27.94,27.78,27.65,26.35,26.25。 13 C NMR (101MHz, CDCl 3 ) δ151.55,147.96,137.39,136.72,136.65,128.98,128.13,126.59,125.10,125.05,123.61,122.42,102.96,99.95,81.42,77.64,77.59,73.01,70.08,60.92,58.91 , 54.31, 50.93, 37.26, 35.48, 32.48, 30.97, 30.92, 29.94, 29.71,28.08, 27.94, 27.78, 27.65, 26.35, 26.25.
31P{ 1H}NMR(162MHz,CDCl 3)δ57.20。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 57.20.
实施例59.[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(2’-氨基联苯-2-η 2-C,N)氯化钯(II) Example 59. [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]- (2'-Aminobiphenyl-2-η 2 -C, N) Palladium (II) chloride
Figure PCTCN2019088461-appb-000078
Figure PCTCN2019088461-appb-000078
称取476mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与308.9mg的二聚(2’-氨基联苯-2-η 2-C,N)氯化钯,抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应2小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.7g黄色固体,产率89％。 Weigh 476mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine and 308.9mg The dimerized (2'-aminobiphenyl-2-η 2 -C, N) palladium chloride was pumped and ventilated three times, 10 mL of degassed anhydrous dichloromethane was injected, and the reaction was stirred for 2 hours. Filtration and separation and purification by silica gel column chromatography gave 0.7g yellow solid with a yield of 89%.
31P{ 1H}NMR(162MHz,CDCl 3)δ41.38,33.40。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 41.38, 33.40.
实施例60.[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(2’-甲氨基联苯-2-η 2-C,N)-甲磺酸钯(II) Example 60. [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]- (2'-Methylaminobiphenyl-2-η 2 -C, N) -palladium (II) methanesulfonate
Figure PCTCN2019088461-appb-000079
Figure PCTCN2019088461-appb-000079
称取476mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与382mg的二聚(2’-甲氨基联苯-2-η 2-C,N)-甲磺酸钯(II),抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.76g黄色固体,产率88％。 Weigh 476mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -dicyclohexylphosphine and 382mg Dimerize (2'-methylaminobiphenyl-2-η 2 -C, N) -palladium (II) methanesulfonate, evacuate three times, inject 10 mL of degassed anhydrous dichloromethane, and stir for 1 hour Filtered through diatomaceous earth and purified by silica gel column chromatography to obtain 0.76g of yellow solid with a yield of 88%.
31P{ 1H}NMR(162MHz,CDCl 3)δ59.58。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 59.58.
实施例61.[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(η 3-烯丙基)-氯化钯(II) Example 61. [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]- (η 3 -allyl) -palladium (II) chloride
Figure PCTCN2019088461-appb-000080
Figure PCTCN2019088461-appb-000080
称取476mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与183mg的二聚烯丙基氯化钯,抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.6g黄色固体,产率90％。Weigh 476mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine and 183mg Diallyl palladium chloride, pumped and ventilated three times, injected with 10 mL of degassed anhydrous dichloromethane, and stirred for 1 hour. Filtered through celite and purified by silica gel column chromatography to obtain 0.6 g of a yellow solid. The yield is 90%.
31P{ 1H}NMR(162MHz,CDCl 3)δ30.50. 31 P { 1 H} NMR (162MHz, CDCl 3 ) δ30.50.
HRMS(ESI)理论值C 33H 54ClO 5PPd+H +:623.2143.实测值:623.2139。 HRMS (ESI) theoretical value C 33 H 54 ClO 5 PPd + H + : 623.2143. Found: 623.2139.
实施例62.(R p)-[(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-苯基膦]-(N,N-二甲基苯甲胺-2-η 2-C,N)-氯化钯(II) Example 62. (R p )-[(methyl 3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -phenylphosphine]-(N, N-dimethylbenzylamine-2-η 2 -C, N) -palladium (II) chloride
Figure PCTCN2019088461-appb-000081
Figure PCTCN2019088461-appb-000081
称取374mg的(甲基3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-苯基膦与268.5mg的二聚[(N,N-二甲基苯甲胺基-2-η 2-C,N)-PdCl(II)],抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应2小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.7g黄色固体,产率93％。 Weigh 374mg of (methyl 3-deoxy-4, 6-oxo-benzylidene-ɑ-D-azandranosidyl-3) -phenylphosphine and 268.5mg of dimerized ((N, N -Dimethylbenzylamino-2-η 2 -C, N) -PdCl (II)], pumping and ventilating three times, injecting 10 mL of degassed anhydrous dichloromethane, and stirring to react for 2 hours. The soil was filtered and separated and purified by silica gel column chromatography to obtain 0.7 g of a yellow solid with a yield of 93%.
1H NMR(400MHz,CDCl 3)δ7.91(dd,J＝12.3,7.3Hz,2H),7.38–7.11(m,8H),7.08–6.97(m,3H),6.77(d,J＝7.5Hz,2H),6.02(d,J＝9.6Hz,1H),5.49–5.36(m,2H),5.05(d,J＝9.6Hz,1H),4.77(s,1H),4.52(ddd,J＝20.0,9.8,6.1Hz,1H),4.34(dd,J＝10.4,4.9Hz,1H),4.17(td,J＝10.1,5.2Hz,1H),3.99–3.83(m,4H),3.73(dd,J＝16.4,10.3Hz,1H),3.19(s,3H),2.76(dd,J＝32.9,2.3Hz,6H),2.28(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (dd, J = 12.3, 7.3 Hz, 2H), 7.38–7.11 (m, 8H), 7.08–6.97 (m, 3H), 6.77 (d, J = 7.5 Hz, 2H), 6.02 (d, J = 9.6Hz, 1H), 5.49-5.36 (m, 2H), 5.05 (d, J = 9.6Hz, 1H), 4.77 (s, 1H), 4.52 (ddd, J = 20.0, 9.8, 6.1 Hz, 1H), 4.34 (dd, J = 10.4, 4.9 Hz, 1H), 4.17 (td, J = 10.1, 5.2 Hz, 1H), 3.99–3.83 (m, 4H), 3.73 ( dd, J = 16.4, 10.3 Hz, 1H), 3.19 (s, 3H), 2.76 (dd, J = 32.9, 2.3 Hz, 6H), 2.28 (s, 1H).
13C NMR(101MHz,CDCl 3)δ148.39,136.77,134.34,134.15,132.76,132.66,130.86,130.37,129.67,128.50,128.39,127.72,125.86,125.79,125.73,124.41, 122.96,101.47,100.68,77.39,77.07,76.75,75.95,75.87,72.29,71.72,71.58,69.24,60.32,54.67,50.40,50.29,40.04,39.81。 13 C NMR (101 MHz, CDCl 3 ) δ 148.39, 136.77, 134.34, 134.15, 132.76, 132.66, 130.86, 130.37, 129.67, 128.50, 128.39, 127.72, 125.86, 125.79, 125.73, 124.41, 122.96, 101.47, 100.68, 77.39, 77.07 , 76.75, 75.95, 75.87, 72.29, 71.72, 71.58, 69.24, 60.32, 54.67, 50.40, 50.29, 40.04, 39.81.
31P{ 1H}NMR(162MHz,CDCl 3)δ17.64。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 17.64.
HRMS(ESI)理论值C 29H 35ClNO 5PPd-Cl -+H +:615.1371.实测值:615.1360。 HRMS (ESI) theory C 29 H 35 ClNO 5 PPd- Cl - + H +:. 615.1371 . Found: 615.1360.
实施例63.反式-{双[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-二氯化钯(II)}Example 63. Trans- {bis [(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranosyl-3) -di Cyclohexylphosphine] -Palladium (II) dichloride}
Figure PCTCN2019088461-appb-000082
Figure PCTCN2019088461-appb-000082
称取476mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与262mg的二聚2-苯基乙胺氯化钯,抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.53g黄色固体,产率73％。Weigh 476mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine and 262mg Dimer 2-phenylethylamine palladium chloride, pumping and ventilating three times, injecting 10mL of degassed anhydrous dichloromethane, stirring and reacting for 1 hour. Filtration through celite, separation and purification by silica gel column chromatography to obtain 0.53g Yellow solid, yield 73%.
31P{ 1H}NMR(162MHz,CDCl 3)δ26.73。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 26.73.
实施例64.[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]-(2’-氨基苯乙烷-2-η 2-C,N)-氯化钯(II) Example 64. [(Methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-azopyranoside-3) -dicyclohexylphosphine]- (2'-aminophenylethane-2-η 2 -C, N) -palladium (II) chloride
Figure PCTCN2019088461-appb-000083
Figure PCTCN2019088461-appb-000083
称取476mg的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与262mg的二聚(2’-氨基苯乙烷-2-η 2-C,N)-氯化钯(II),抽换气三次,注入10mL的脱气的无水二氯甲烷,搅拌反应1小时.经硅藻土过滤,硅胶柱层析分离提纯,得到0.53g黄色固体,产率73％。 Weigh 476mg of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeptoside-3) -dicyclohexylphosphine and 262mg Dimerize (2'-aminophenylethane-2-η 2 -C, N) -palladium (II) chloride, evacuate three times, inject 10 mL of degassed anhydrous dichloromethane, and stir the reaction for 1 hour. After filtration through celite and separation and purification by silica gel column chromatography, 0.53 g of yellow solid was obtained with a yield of 73%.
31P{ 1H}NMR(162MHz,CDCl 3)δ40.12。 31 P { 1 H} NMR (162 MHz, CDCl 3 ) δ 40.12.
实施例65-72.Examples 65-72.
Suzuki偶联反应的常规操作说明.在氮气氛围下,将1.0mmol芳基卤化物、1.5mmol硼酸、3.0mmol K 3PO 4、适量的催化剂、75uL的十二烷(作为GC分析的内标)和1.5mL无水甲苯置于压力管中.将该管密封并置于适宜的温度中,反应数小时.加入二氯甲烷并硅藻土助滤.用气相色谱分析得到卤代烃的转化率.通过(石油醚/乙酸乙酯)硅胶柱层析提纯偶联产物。 General operation instructions of Suzuki coupling reaction. Under a nitrogen atmosphere, 1.0 mmol of aryl halide, 1.5 mmol of boric acid, 3.0 mmol of K 3 PO 4 , an appropriate amount of catalyst, and 75 uL of dodecane (as an internal standard for GC analysis) And 1.5mL of anhydrous toluene was placed in a pressure tube. The tube was sealed and placed at a suitable temperature and reacted for several hours. Dichloromethane was added and filtered through diatomaceous earth. The conversion rate of halogenated hydrocarbon was obtained by gas chromatography analysis . Purify the coupling product by (petroleum ether / ethyl acetate) silica gel column chromatography.
催化剂为[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦]-(N,N-二甲基苯甲胺基-2-η 2-C,N)-氯化钯(II)。 The catalyst is [(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3) -dicyclohexylphosphine]-(N , N-dimethylbenzylamino-2-η 2 -C, N) -palladium (II) chloride.
Figure PCTCN2019088461-appb-000084
Figure PCTCN2019088461-appb-000084
实施例73-85.Examples 73-85.
Buchwald-Hartwig胺化偶联反应的操作说明。在压力管中,在氮气氛围下,将1.0mmol芳基卤化物、1.2mmol胺、1.2mmol叔丁醇钠、适量的催化剂和75uL的十二烷(作为GC分析的内标)溶于1.5mL无水甲苯中.将该管密封并置于120℃中,反应数小时.加入二氯甲烷并硅藻土助滤.用气相色谱分析.通过(石油醚/乙酸乙酯)柱层析分离产物。Instructions for the Buchwald-Hartwig amination coupling reaction. In a pressure tube, under a nitrogen atmosphere, dissolve 1.0 mmol of aryl halide, 1.2 mmol of amine, 1.2 mmol of sodium tert-butoxide, an appropriate amount of catalyst, and 75 uL of dodecane (as an internal standard for GC analysis) in 1.5 mL In anhydrous toluene. The tube was sealed and placed at 120 ° C. for several hours. Add dichloromethane and filter aid with diatomaceous earth. Analyze by gas chromatography. Isolate the product by (petroleum ether / ethyl acetate) column chromatography .
催化剂为{(N,N-二甲基苯甲胺基-2-η 2-C,N)-[(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-阿卓吡喃糖苷基-3)-二环己基膦]氯化钯(II)}。 The catalyst is {(N, N-dimethylbenzylamino-2-η 2 -C, N)-[(methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene Group-ɑ-D-azopyranoside-3) -dicyclohexylphosphine] palladium (II) chloride}.
Figure PCTCN2019088461-appb-000085
Figure PCTCN2019088461-appb-000085
实施例86-90Examples 86-90
在氮气氛围下,先将适量的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与Pd(OAc) 2在甲苯中混合搅拌10分钟(配体:Pd(OAc) 2＝2:1)原位制得催化剂,待用。 Under a nitrogen atmosphere, first apply an appropriate amount of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -bicyclo The hexylphosphine and Pd (OAc) 2 were mixed and stirred in toluene for 10 minutes (ligand: Pd (OAc) 2 = 2: 1). The catalyst was prepared in situ and was ready for use.
在氮气氛围下,将1.0mmol芳基卤化物、1.5mmol硼酸、3.0mmol K 3PO 4、适量的催化剂、75uL的十二烷(作为GC分析的内标)和1.5mL无水甲苯置于压力管中.将该管密封并置于适宜的温度中,反应数小时.加入二氯甲烷并硅藻土助滤.用气相色谱分析得到卤代烃的转化率.通过(石油醚/乙酸乙酯)硅胶柱层析提纯偶联产物。 Under a nitrogen atmosphere, place 1.0 mmol of aryl halide, 1.5 mmol of boric acid, 3.0 mmol of K 3 PO 4 , an appropriate amount of catalyst, 75 uL of dodecane (as an internal standard for GC analysis), and 1.5 mL of anhydrous toluene under pressure The tube was sealed and placed at a suitable temperature for a few hours of reaction. Dichloromethane was added and diatomite was used for filtration aid. The conversion rate of halogenated hydrocarbon was obtained by gas chromatography analysis. Pass (petroleum ether / ethyl acetate) ) Silica gel column chromatography to purify the coupled product.
Figure PCTCN2019088461-appb-000086
Figure PCTCN2019088461-appb-000086
实施例91.Example 91.
在氮气氛围下,先将适量的(甲基2-氧-甲基-3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3)-二环己基膦与Pd(OAc) 2在甲苯中混合搅拌10分钟(配体:Pd(OAc) 2＝2:1)制得催化剂,待用。 Under a nitrogen atmosphere, first apply an appropriate amount of (methyl 2-oxo-methyl-3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azeposide-3) -bicyclo The hexylphosphine and Pd (OAc) 2 were mixed and stirred in toluene for 10 minutes (ligand: Pd (OAc) 2 = 2: 1) to prepare a catalyst, which was ready for use.
在压力管中,在氮气氛围下,将1.0mmol芳基卤化物、1.2mmol胺、1.2mmol叔丁醇钠、适量的催化剂和75uL的十二烷(作为GC分析的内标)溶于1.5mL无水甲苯中。将该管密封并置于120℃中,反应数小时。加入二氯甲烷并硅藻土助滤.用气相色谱分析.通过(石油醚/乙酸乙酯)柱层析分离产物。In a pressure tube, under a nitrogen atmosphere, dissolve 1.0 mmol of aryl halide, 1.2 mmol of amine, 1.2 mmol of sodium tert-butoxide, an appropriate amount of catalyst, and 75 uL of dodecane (as an internal standard for GC analysis) in 1.5 mL In anhydrous toluene. The tube was sealed and placed at 120 ° C for a few hours. Dichloromethane was added and filtered through celite. Analysis by gas chromatography. The product was isolated by (petroleum ether / ethyl acetate) column chromatography.
Figure PCTCN2019088461-appb-000087
Figure PCTCN2019088461-appb-000087

Claims (10)

  1. 具有通式Ia、Ib、IIa或IIb的碳水化合物单膦，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物:Carbohydrate monophosphines having the general formula Ia, Ib, IIa or IIb, including mixtures of Ia and Ib with different phosphorus atom configurations or mixtures of IIa and IIb with different phosphorus atom configurations:
    Figure PCTCN2019088461-appb-100001
    Figure PCTCN2019088461-appb-100001
    其中，among them,
    碳水化合物单元可以是ɑ-D-吡喃阿卓糖、β-D-吡喃阿卓糖、ɑ-D-吡喃艾杜糖或β-D-吡喃艾杜糖单元；The carbohydrate unit may be an ɑ-D-aradanose, β-D-aradanose, ɑ-D-iduran or β-D-idulan unit;
    R 1选自H、(C1-C6)烷基、(C6-C10)芳基或-CH 2(C6-C10)芳亚甲基，这里的(C6-C10)芳基和-CH 2(C6-C10)芳亚甲基可以有1到3个独立地选自硝基、(C1-C6)烷基或-O(C1-C6)烷氧基的取代基； R 1 is selected from H, (C1-C6) alkyl, (C6-C10) aryl or -CH 2 (C6-C10) aryl methylene, here (C6-C10) aryl and -CH 2 (C6 -C10) arylmethylene may have 1 to 3 substituents independently selected from nitro, (C1-C6) alkyl or -O (C1-C6) alkoxy;
    Figure PCTCN2019088461-appb-100002
    Figure PCTCN2019088461-appb-100002
    R 2和R 3各自独立地选自H、(C1-C6)烷基、(C1-C8)酰基或-CH 2(C6-C10)芳亚甲基，或者R 2和R 3组合为甲叉基＝CR 7R 8，这里的R 7和R 8可各自独立地选自H、(C1-C6)烷基、(5到6元的)环烷基或(C6-C10)芳基； R 2 and R 3 are each independently selected from H, (C1-C6) alkyl, (C1-C8) acyl or -CH 2 (C6-C10) aryl methylene, or R 2 and R 3 are combined to form methylene Radical = CR 7 R 8 , where R 7 and R 8 may each be independently selected from H, (C1-C6) alkyl, (5- to 6-membered) cycloalkyl or (C6-C10) aryl;
    R 4和R 5各自独立地选自H、OH、SH、(C1-C8)烷基、(C3-C10)环烷基、(5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基、二茂铁基或R 4和R 5组合为9-磷杂芴基，但R 4和R 5之一选自H、OH或SH时另一个R 4或R 5则不能为H、OH或SH，这里的(C3-C10)环烷基、(5-6元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基、二茂铁基、-CH 2(C6-C10)芳亚甲基和9-磷杂芴基中可以有1到3个独立地选自(C1-C6)烷基(可以带F原子)、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷基氨基的取代基，而(5-6元)杂环烷基和(C4-C20)杂芳基中的杂原子选自O、N或S； R 4 and R 5 are each independently selected from H, OH, SH, (C1-C8) alkyl, (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aromatic Group, (C4-C20) heteroaryl, ferrocenyl or R 4 and R 5 are combined as 9-phosphafluorenyl, but one of R 4 and R 5 is selected from H, OH or SH, the other R 4 Or R 5 can not be H, OH or SH, here (C3-C10) cycloalkyl, (5-6 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl , Ferrocenyl, -CH 2 (C6-C10) arylmethylene and 9-phosphafluorenyl can have 1 to 3 independently selected from (C1-C6) alkyl (may have F atoms), -O (C1-C6) alkoxy or -N (C1-C6) 2 dialkylamino substituent, and (5-6 member) heterocycloalkyl and (C4-C20) heteroaryl The atom is selected from O, N or S;
    Figure PCTCN2019088461-appb-100003
    Figure PCTCN2019088461-appb-100003
    R 6选自H、(C1-C6)烷基、(C1-C8)酰基、-CH 2(C6-C10)芳亚甲基或R 9SO 2磺酰基，这里的R 9选自(C1-C6)烷基或(C6-C10)芳基； R 6 is selected from H, (C1-C6) alkyl, (C1-C8) acyl, -CH 2 (C6-C10) arylmethylene or R 9 SO 2 sulfonyl, where R 9 is selected from (C1- C6) alkyl or (C6-C10) aryl;
    当碳水化合物单元为(甲基2-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-2-)时：且R 4和R 5均为苯基时，R 6则不为H； When the carbohydrate unit is (methyl 2-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosid-2-): and when R 4 and R 5 are both phenyl , R 6 is not H;
    当碳水化合物单元为甲基(3-脱氧-4,6-氧-苯甲叉基-ɑ-D-吡喃阿卓糖苷基-3-)时：1)且R 4和R 5均为苯基时，R 6则不为H或甲基；2)且R 4为苯基而同时R 5为甲基时，R 6则不为H或甲基；3)且R 4为苯基同时R 5为H时，R 6则不为H。 When the carbohydrate unit is methyl (3-deoxy-4,6-oxo-benzylidene-ɑ-D-pyran azreosidino-3-): 1) and R 4 and R 5 are both benzene when the group, R 6 is not H or methyl; 2) and R 4 is phenyl while R 5 is a methyl group, R 6 is not H or methyl; 3) and R 4 is phenyl while R When 5 is H, R 6 is not H.
  2. 根据权利要求1所述的碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 1可精选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、苯基、对甲苯基、对硝基苯基、对甲氧基苯基、萘基、苯基亚甲基、对甲苯基亚甲基、对甲氧基苯基亚甲基或萘基亚甲基。 The carbohydrate monophosphine according to claim 1, having the general formula Ia, Ib, IIa or IIb, including a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 1 Can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl, p-tolyl, p-nitrophenyl, p-methoxyphenyl, Naphthyl, phenylmethylene, p-tolylmethylene, p-methoxyphenylmethylene or naphthylmethylene.
  3. 根据上述权利要求所述的碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 2或R 3可以独立地进一步选自甲基、乙基、正丙基、正丁基、正戊基、正己基、苯亚甲基、对甲基苯亚甲基、对甲氧基苯亚甲基、萘亚甲基、甲酰基、乙酰基、丙酰基、苯甲酰基或苯乙酰基，或者R 2和R 3组合为甲叉基＝CR 7R 8时，R 7和R 8可独立地选自H、甲基、乙基、丙基、丁基、环戊基、环己基、苯基、对甲苯基、对甲氧基苯基或萘基。 The carbohydrate monophosphine according to the preceding claims, having the general formula Ia, Ib, IIa or IIb, comprising a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 2 or R 3 may independently be further selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, benzylidene, p-toluenemethylene, p-methoxybenzylidene When methyl, naphthalene methylene, formyl, acetyl, propionyl, benzoyl or phenylacetyl, or R 2 and R 3 are combined as methylene = CR 7 R 8 , R 7 and R 8 can be independent Groundly selected from H, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, phenyl, p-tolyl, p-methoxyphenyl or naphthyl.
  4. 根据上述权利要求所述的碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 4或R 5可以进一步独立地选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、特戊基、特辛基、环丙基、环丁基、环戊基、环己基、金刚基、 苯基、4-甲苯基、2-甲苯基、2-(二甲氨基)苯基、4-(二甲氨基)苯基、2-甲氧基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、3,5-双三氟甲基苯基、2,6-二甲基苯基、2,6-二甲氧基苯基、2,6-双(二甲氨基)苯基、3,4,5-三甲氧基苯基、2-联苯基、2’-甲基-2-联苯基、2’-异丙基-2-联苯基、2’-甲氧基-2-联苯基、2’-异丙氧基-2-联苯基、2’-二甲氨基-2-联苯基、2’,6’-二甲基-2-联苯基、2’,6’-二异丙基-2-联苯基、2’,4’,6’-三异丙基-2-联苯基、2’,6’-二甲氧基-2-联苯基、2’,6’-二异丙氧基-2-联苯基、2’,6’-双(二甲氨基)-2-联苯基、2,6-二苯基苯基、2,6-双(2’,6’-二甲氧基苯基)苯基、2,6-双(2’,6’-二异丙氧基苯基)苯基、2,6-双(2’,6’-二甲基苯基)苯基、2,6-双(2’,4’,6’-三甲基苯基)苯基、2,6-双(2’,6’-二异丙基苯基)苯基、2,6-双(2’,4’,6’-三异丙基苯基)苯基、萘基、1,1’-2-联萘基、1,1’-2’-甲氧基-2-联萘基、2-呋喃基、2-噻吩基、5-甲基2-呋喃基、5-甲基-2-噻吩基、2-吡啶基、3-吡啶基、8-喹啉基、二茂铁基、乙酰基二茂铁基或(1-二甲基氨基-乙基)二茂铁-2-基。 The carbohydrate monophosphine according to the preceding claims, having the general formula Ia, Ib, IIa or IIb, comprising a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 4 or R 5 may be further independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, t-amyl, t-octyl, cyclopropyl, cyclobutane Group, cyclopentyl, cyclohexyl, adamantyl, phenyl, 4-tolyl, 2-tolyl, 2- (dimethylamino) phenyl, 4- (dimethylamino) phenyl, 2-methoxy Phenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-bistrifluoromethylphenyl, 2,6-dimethyl Phenyl, 2,6-dimethoxyphenyl, 2,6-bis (dimethylamino) phenyl, 3,4,5-trimethoxyphenyl, 2-biphenyl, 2'-methyl Yl-2-biphenyl, 2'-isopropyl-2-biphenyl, 2'-methoxy-2-biphenyl, 2'-isopropoxy-2-biphenyl, 2 ' -Dimethylamino-2-biphenyl, 2 ', 6'-dimethyl-2-biphenyl, 2', 6'-diisopropyl-2-biphenyl, 2 ', 4', 6'-triisopropyl-2-biphenyl, 2 ', 6'-dimethoxy-2-biphenyl, 2', 6'- Isopropoxy-2-biphenyl, 2 ', 6'-bis (dimethylamino) -2-biphenyl, 2,6-diphenylphenyl, 2,6-bis (2', 6 '-Dimethoxyphenyl) phenyl, 2,6-bis (2', 6'-diisopropoxyphenyl) phenyl, 2,6-bis (2 ', 6'-dimethyl Phenyl) phenyl, 2,6-bis (2 ', 4', 6'-trimethylphenyl) phenyl, 2,6-bis (2 ', 6'-diisopropylphenyl) benzene Group, 2,6-bis (2 ', 4', 6'-triisopropylphenyl) phenyl, naphthyl, 1,1'-2-binapthyl, 1,1'-2'-methyl Oxy-2-binaphthyl, 2-furyl, 2-thienyl, 5-methyl 2-furyl, 5-methyl-2-thienyl, 2-pyridyl, 3-pyridyl, 8- Quinolinyl, ferrocenyl, acetylferrocenyl or (1-dimethylamino-ethyl) ferrocen-2-yl.
  5. 根据上述权利要求所述的碳水化合物单膦，具有通式Ia、Ib、IIa或IIb，包括磷原子构型不同的Ia和Ib的混合物或者磷原子构型不同的IIa和IIb的混合物，其中R 6是可精选自甲基、乙基、正丙基、正丁基、正戊基、正己基、苯甲基、4-甲氧基苯甲基、萘甲基、甲酰基、乙酰基、丙酰基、苯甲酰基、苯乙酰基、甲磺酰基、苯甲磺酰基或对甲苯磺酰基。 The carbohydrate monophosphine according to the preceding claims, having the general formula Ia, Ib, IIa or IIb, comprising a mixture of Ia and Ib with different phosphorus atom configurations or a mixture of IIa and IIb with different phosphorus atom configurations, wherein R 6 can be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, benzyl, 4-methoxybenzyl, naphthylmethyl, formyl, acetyl, Propionyl, benzoyl, phenylacetyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
  6. 根据权利要求1至5项中一项所述的碳水化合物单膦的制备方法，其特征有：1)用膦负离子与吡喃碳水化合物2,3-环氧化物发生亲核开环反应来作为制备碳水化合物单膦的关键反应步骤；2)当由亲核开环制得的膦中的磷原子带一个氢原子时，可被碱拔去形成膦负离子再与亲电试剂发生亲核取代反应，或在钯或镍催化下与氯、溴或碘代芳烃发生C-P键形成反应，来进一步制得磷原子上带其它取代基的衍生物；3)当所制备的膦中碳水化合物骨架上带有羟基时，可由缩醛(酮)化、亲核取代反应或酯化反应制得羟基缩醛(酮)化、醚化或酯化的衍生物；4)有时为了制备反应的需要或分离操作的方便，会加入硼烷的四氢呋喃或二甲硫醚加合物来形成膦的硼烷加合物。而脱除膦的硼烷加合物中的硼烷可以在含有或不含有胺如二乙胺、二异丙胺、吗啡啉、或三乙烯二胺的醇溶剂中，在50到130℃的反应温度下实现。The method for preparing a carbohydrate monophosphine according to one of claims 1 to 5, characterized in that: 1) a nucleophilic ring-opening reaction of phosphine anion and pyran carbohydrate 2,3-epoxide is used as The key reaction steps for the preparation of carbohydrate monophosphine; 2) When the phosphorus atom in the phosphine prepared by nucleophilic ring opening has a hydrogen atom, it can be pulled out by alkali to form a phosphine anion and then undergo a nucleophilic substitution reaction with the electrophilic reagent , Or under the catalysis of palladium or nickel with chlorine, bromine or iodo aromatic hydrocarbons to form a CP bond reaction to further prepare derivatives with other substituents on the phosphorus atom; 3) When the carbohydrate skeleton in the prepared phosphine has In the case of hydroxyl group, hydroxyacetal (ketone), etherified or esterified derivatives can be prepared by acetal (ketone), nucleophilic substitution reaction or esterification; 4) Sometimes for the purpose of preparation reaction or separation operation Conveniently, a tetrahydrofuran or dimethyl sulfide adduct of borane is added to form a borane adduct of phosphine. The borane in the phosphine-removing borane adduct can be reacted in an alcoholic solvent with or without amines such as diethylamine, diisopropylamine, morpholine, or triethylenediamine at 50 to 130 ° C. At temperature.
  7. 根据权利要求1至5项中一项所述的碳水化合物单膦的硼烷加合物、氧 化物(P＝O)、硫化物(P＝S)或硒化物(P＝Se)，此时R 4或R 5不为OH或SH。 The borane adduct, oxide (P = O), sulfide (P = S) or selenide (P = Se) of the carbohydrate monophosphine according to one of claims 1 to 5, in this case R 4 or R 5 are not OH or SH.
  8. 具有通式XI、XII、XIII、XIV或XV的碳水化合物单膦配位的钯络合物：Palladium complexes with carbohydrate monophosphine coordination of the general formula XI, XII, XIII, XIV or XV:
    Figure PCTCN2019088461-appb-100004
    Figure PCTCN2019088461-appb-100004
    其中L为上面定义的碳水化合物单膦；X 3和X 7可独立地选自Cl、Br或I；X 4、X 5和X 6可独立地选自Cl、Br、I、甲磺酸基、苯磺酸基、对甲苯磺酸基、甲酸基、乙酸基或苯甲酸基；R 10、R 11、R 12、R 13和R 14各自独立地选自H、甲基或苯基。 Where L is a carbohydrate monophosphine as defined above; X 3 and X 7 can be independently selected from Cl, Br or I; X 4 , X 5 and X 6 can be independently selected from Cl, Br, I, mesylate , Benzenesulfonate, p-toluenesulfonate, formate, acetate or benzoate; R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from H, methyl or phenyl.
  9. 根据权利要求1至5项中一项所述的碳水化合物单膦和元素周期表VIII副族的过渡金属盐或络合物结合形成的体系用作催化剂的用途，其中，通常将所述膦原位加入到合适的过渡金属前体化合物的体系中或将所述的碳水化合物单膦直接与过渡金属配位形成络合物。其特征在于所用的过渡金属是钯、镍、铂、铑、钴、铱和钌，优选的过渡金属是钯或镍。The use of a system formed by combining a carbohydrate monophosphine according to one of claims 1 to 5 with a transition metal salt or complex of Subgroup VIII of the periodic table as a catalyst, wherein the phosphine is generally used Into the system of suitable transition metal precursor compounds or coordinate the carbohydrate monophosphine directly with the transition metal to form a complex. It is characterized in that the transition metals used are palladium, nickel, platinum, rhodium, cobalt, iridium and ruthenium, and the preferred transition metals are palladium or nickel.
  10. 根据权利要求9所述的用途,其特征在于所述的膦配体用于催化(拟)卤代芳烃为底物去形成新的C-C、或C-N键的偶联反应中。The use according to claim 9, characterized in that the phosphine ligand is used to catalyze the coupling reaction of (pseudo) halogenated aromatic hydrocarbon as a substrate to form a new C-C or C-N bond.
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