WO2018205108A1 - 一种酰胺醇解的方法 - Google Patents

一种酰胺醇解的方法 Download PDF

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WO2018205108A1
WO2018205108A1 PCT/CN2017/083498 CN2017083498W WO2018205108A1 WO 2018205108 A1 WO2018205108 A1 WO 2018205108A1 CN 2017083498 W CN2017083498 W CN 2017083498W WO 2018205108 A1 WO2018205108 A1 WO 2018205108A1
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amide
alcoholysis
product
group
mmol
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PCT/CN2017/083498
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English (en)
French (fr)
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卢江平
裴青蓝
余金权
张恩选
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凯莱英医药集团（天津）股份有限公司
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Priority to US16/609,237 priority Critical patent/US10696617B2/en
Priority to PCT/CN2017/083498 priority patent/WO2018205108A1/zh
Publication of WO2018205108A1 publication Critical patent/WO2018205108A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
    • C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C07D209/49—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the field of organic material synthesis, and in particular to a method for amide alcoholysis.
  • an amide bond is widely present in natural products such as proteins and synthetic compounds. It is generally believed that the resonance stability of the amide bond makes the amide a weaker electrophile (The structure of proteins: two hydrogenbonded helical configurations of the polypeptide chain. Proc. Natl. Acad. Sci. 1951, 37, 205), and so on It is difficult to chemically synthesize the amides to esters by the nickel-catalysed activation of amide C-N bonds. Nature 2015, 524, 79.
  • the above reaction using BF 3 ⁇ Et 2 O at 100 ° C to achieve alcoholysis of the targeting group has the disadvantages of relatively expensive reagents, complicated operation, and severe reaction conditions.
  • the remaining methods described above require strong acid or base conditions and many functional groups are not stable under these conditions. Moreover, the above methods are all affected by the substrate steric hindrance, and the substrate has a small application range.
  • the main object of the present invention is to provide a method for amide alcoholysis to solve the problems of complicated operation and harsh reaction conditions of the amide alcoholysis method in the prior art.
  • a process for the amide alcoholysis which comprises using an epoxy compound as an alcoholysis promoter to subject an amide-containing compound to alcoholysis under basic conditions.
  • the epoxy compound and the amide compound are used in an amount of from 1 to 5:1 in terms of a molar ratio of the epoxy compound to the amide compound.
  • the above amide-containing compound has the formula I, and the formula I is R 1 and R 2 are each independently selected from any one of an alkyl group, an aryl group, a substituted alkyl group and a substituted aryl group, and preferably the alkyl group is selected from any one of C 1 -C 18 alkyl groups, preferably substituted.
  • the alkyl group has a main chain carbon number of any one of C 1 to C 18 , and preferably the substituted alkyl group is a monosubstituted alkyl group or a polysubstituted alkyl group.
  • the substituent in the substituted alkyl group is selected from the group consisting of an aryl group and an aromatic group. a combination substituent of any one or more of a ring substituent, a cycloalkane, a heterocycloalkane, an alkenyl group, and an alkynyl group.
  • the above epoxy compound has the general formula II, and the general formula II is R 3 and R 4 are each independently selected from any of H, an alkyl group and an aryl group, and preferably the alkyl group is selected from any one of C 1 - C 18 alkyl groups.
  • the above method comprises: mixing an amide-containing compound, an epoxy compound, a pH adjuster, and a solvent to form an alkaline reaction system, preferably a pH of a basic reaction system of 7.5 to 9.5; and an alkaline reaction system of 50 The reaction is carried out at -150 ° C to effect alcoholysis on the amide-containing compound.
  • the pH adjusting agent is a weak acid or a weak base, and preferably the pH adjusting agent is selected from the group consisting of CF 3 CO 2 K, CF 3 CO 2 Na, CsOAc, KOAc, NaOAc, LiOAc, CsHCO 3 , KHCO 3 , NaHCO 3 , LiHCO 3 , CsF, KF, NaF, LiF, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 , K 2 HPO 4 , Na 2 HPO 4 , Li 2 HPO 4 , K 3 PO 4 Any one or more of Na 3 PO 4 , sodium benzoate, tetramethylethylenediamine, NN diisopropylethylamine, and triethylamine.
  • the above solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, ethylene glycol, glycerol, 1,2-dimethoxy Any one or more of ethyl ethane, ethylene glycol diethyl ether, 2-methoxyethyl ether, 2-ethoxyethyl ether, and pyrrole.
  • the above amide-containing compound is
  • the epoxy compound is methyl glycidyl ether
  • the pH adjuster is KOAc
  • the solvent is ethanol.
  • the method further comprises: dehydrating the alcoholysis product to obtain a residue; mixing the residue with water to form a mixture; adjusting the pH of the mixture to 3.5 to 4.5, using n-hexane The extraction is carried out to obtain an organic phase; and the organic phase is dried and filtered.
  • the method further comprises: dehydrating the alcoholysis product to a solvent to obtain a residue; and purifying the residue by silica gel column chromatography.
  • the above method is not only easy to operate, but also requires a simple conventional separation step to obtain a pure product, and at the same time, since the cost of the epoxy compound is low, the production operation cost and the three waste treatment can be greatly reduced. Risks and costs.
  • the reaction conditions are mild, and it is compatible with various substituents and The functional group can obtain good yield for amides of various structural types, and the substrate has a wide application range. That is, the present invention provides an environmentally friendly, economical and efficient method for the alcoholysis of the amide.
  • the above alcoholysis reaction of the present application is not affected by the impurities in the C-H activation reaction system of the previous step, and the intermediate purification step is saved, and the C-H activation and the amido alcoholysis two-step reaction can be continuously administered.
  • the present application provides a method for amide alcoholysis, which comprises using an epoxy compound as a promoter. The amide-containing compound is subjected to alcoholysis under alkaline conditions.
  • the inventors of the present application have unexpectedly discovered that the use of an alcohol solution of an epoxy compound under alkaline conditions can promote the conversion of an amide to an ester, and an amide NH having a certain acidity under alkaline conditions.
  • the nucleophilic attack opens the ring of the activated alkylene oxide to form an N-addition transition state product.
  • the transition state is unstable.
  • the above method is not only easy to operate, but also requires a simple conventional separation step to obtain a pure product, and since the epoxy compound is low in cost, the production operation cost and the risk and cost of the three waste treatment can be greatly reduced.
  • the reaction conditions are mild, and it is compatible with various substituents and functional groups, and the amides of various structural types can be obtained with good yield, and the substrate has a wide application range. That is, the present invention provides an environmentally friendly, economical and efficient method for the alcoholysis of amides.
  • the above alcoholysis reaction of the present application is not affected by the impurities in the C-H activation reaction system of the previous step, and the intermediate purification step is saved, and the two-step reaction of C-H activation and amide alcoholysis can be continuously administered.
  • the ratio of the epoxy compound to the amide-containing compound is from 1 to 5:1 in terms of the molar ratio of the epoxy compound to the amide compound.
  • the ratio of the epoxy compound to the amide-containing compound is more than 5:1, alcoholysis can be achieved, but more epoxy compounds are not involved in the reaction, resulting in waste of raw materials.
  • the method of the present application has a wide substrate universality and is not affected by the steric hindrance effect, and almost all the amide substrates of the structure can be smoothly reacted to obtain a good yield.
  • the amide-containing compound has the general formula I.
  • R 1 and R 2 are each independently selected from any one of an alkyl group, an aryl group, a substituted alkyl group and a substituted aryl group, and preferably the alkyl group is selected from any one of C 1 -C 18 alkyl groups, preferably substituted.
  • the alkyl group has a main chain carbon number of any one of C 1 to C 18 , and preferably the substituted alkyl group is a monosubstituted alkyl group or a polysubstituted alkyl group.
  • the substituent in the substituted alkyl group is selected from the group consisting of an aryl group and an aromatic group.
  • a combination substituent of any one or more of a ring substituent, a cycloalkane, a heterocycloalkane, an alkenyl group and an alkynyl group, and the substituent in the above substituted aryl group may be a halogen, an alkyl group, a substituted alkyl group or the like, such as R 2 is
  • the reaction process of the amide-containing compound having the above general structure requires a milder reaction temperature and a shorter reaction time, and is more suitable for industrial large-scale applications.
  • the above epoxy compound has the general formula II, and the general formula II is R 3 and R 4 are each independently selected from any one of H, an alkyl group and an aryl group, and it is preferred that the above alkyl group is selected from any one of C 1 - C 18 alkyl groups.
  • the specific implementation process can refer to the alcoholysis process in the prior art.
  • the above method comprises: mixing an amide-containing compound, an epoxy compound, a pH adjuster and a solvent.
  • An alkaline reaction system is formed; the basic reaction system is reacted at 50 to 150 ° C to carry out alcoholysis of the amide-containing compound.
  • the pH of the basic reaction system is 7.5 to 9.5.
  • the alkaline reaction system is adjusted by a pH adjuster to facilitate subsequent and efficient alcoholysis, especially when the pH of the alkaline reaction system is 7.5 to 9.5.
  • the reaction rate is more desirable; then the reaction system can be carried out at a low temperature of 50 to 150 °C. It can be seen from the above process that the method of the present application does not require special expensive reagents, mild reaction conditions, and a wide range of suitable substrates, and a wide application range.
  • the pH adjusting agent required for the above pH does not require a strong acid and a strong base, and is preferably a weak acid or a weak base. Further preferably, the pH adjusting agent is selected from the group consisting of CF 3 CO 2 K, CF 3 CO 2 Na, CsOAc, KOAc, NaOAc, LiOAc.
  • the solvent of the present application can refer to the solvent type commonly used in the prior art amide alcoholysis.
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and isoamyl alcohol. Any one of ethylene glycol, glycerol, 1,2-dimethoxyethane, ethylene glycol diethyl ether, 2-methoxyethyl ether, 2-ethoxyethyl ether and pyrrole Or a variety.
  • the following reaction principle is further illustrated by using KOAc as a pH adjuster and ethanol as a solvent.
  • the amide NH having a certain acidity is nucleophilicly attacked by potassium ketone under the action of KOAc to form an N-addition.
  • Transition state product the transition state is unstable, after the oxo anion generated in situ after the ring opening of the alkylene oxide nucleophilically attacks the carbonyl bond of the amide bond, the CN bond of the amide group is broken to form an esterified intermediate product, and then The esterification intermediate and the alcohol solvent undergo a transesterification reaction to form a final amide alcoholysis product. See the following chemical reaction process for details:
  • the above amide-containing compound is
  • the epoxy compound is methyl glycidyl ether
  • the pH adjuster is KOAc
  • the solvent is ethanol.
  • the above basic reaction system is reacted at 80 to 100 ° C to carry out alcoholysis of the amide-containing compound.
  • the method further comprises: dehydrating the alcoholysis product to obtain a residue; mixing the residue with water to form a mixture; adjusting the pH of the mixture to 3.5 to 4.5, and then using n-hexane. Extraction, obtaining an organic phase; and drying and filtering the organic phase.
  • Each of the materials used in the above process is a conventional material and therefore does not increase the cost of the method of the present application; moreover, the above process is a routine operation in the purification process and does not increase the complexity of the method of the present application; further, When extracting, the pH value of the mixture is controlled between 3.5 and 4.5, which is beneficial to improve the extraction separation efficiency.
  • the pH value is adjusted to be acidic, the secondary amine structure on the leaving group is salted, and the water solubility of the leaving group is enhanced. Sexuality makes the leaving group by-products easier to remove by washing. If the acidity is stronger, other functional groups on the product may be deteriorated, and at the same time, the reagent is wasted.
  • the method further comprises: dehydrating the alcoholysis product to obtain a residue; and purifying the residue by silica gel column chromatography, the process is suitable for the product of the laboratory small batch test. Separation.
  • the epoxy compounds are as follows:
  • the product structure is as follows:
  • Example 14 A1 B1 K 2 CO 3 Absolute ethanol
  • Example 15 A1 B1 NaHCO 3 Absolute ethanol
  • Example 16 A1 B1 LiOH Absolute ethanol
  • Example 17 A1 B1 NaOAc Absolute ethanol
  • Example 18 A1 B1 KCl Absolute ethanol
  • Example 19 A1 B1 CF 3 COONa Absolute ethanol
  • Example 20 A1 B1 CF 3 COOK Absolute ethanol
  • Example 21 A1 B1 Triethylamine Absolute ethanol
  • Example 22 A1 B1 KOAc Absolute ethanol
  • Example 23 A1 B1 KOAc Absolute ethanol
  • Example 24 A1 B1 KOAc Absolute ethanol
  • Example 25 A1 B1 KOAc Methanol
  • Example 26 A1 B1 KOAc Isopropanol
  • Example 27 A1 B1 KOAc Isobutanol
  • Example 28 A1 B1 KOAc Isoamyl alcohol
  • Example 29 A1 B1 KOAc Absolute ethanol
  • Example 59 A29 B1 KOAc Absolute ethanol
  • Example 60 A1 B2 KOAc Absolute ethanol
  • Example 61 A1 B3 KOAc Absolute ethanol
  • Example 62 A1 B4 KOAc Absolute ethanol
  • Example 63 A1 B5 KOAc Absolute ethanol
  • Example 64 A1 B6 KOAc Absolute ethanol
  • Example 65 A1 B7 KOAc Absolute ethanol
  • Example 66 A1 B8 KOAc Absolute ethanol
  • A1 (87.5 mg, 0.2 mmol), potassium acetate (19.6 mg, 0.2 mmol), absolute ethanol (2.0 mL, water ⁇ 0.01 wt%), methyl group were sequentially added to a 25 mL dry clean Schlenck tube with a magnetic stir bar.
  • Glycidyl ether b1 (52.9 mg, 0.6 mmol) formed a reaction system.
  • the above Schlenck tube was placed in a 90 ° C oil bath and heated for 35 hours. TLC showed the starting material was completely reacted to give the product system.
  • the product system was stopped and heated to cool to room temperature, and the solvent was evaporated under reduced pressure to give a residue, and then, to the residue, 2.0 mL of purified water was added to form a mixture, and the mixture was adjusted to pH 4 with 3M hydrochloric acid, and then n-hexane (3 mL ⁇ ) 3)
  • the organic phase is extracted, and the combined organic phase is dried with anhydrous sodium sulfate. After drying, the mixture is filtered, and the filtrate is concentrated to give a pure product 45.5 mg, yield 92%.
  • the difference from the first embodiment is that after the amount of each material of the embodiment 1 is expanded by 100 times, the alcoholysis reaction is carried out by using a 500 mL pressure reactor, and the filtrate is concentrated to obtain a pure product of 4.648 g, and the yield is 94%.
  • the yield was higher than that of Example 1, because the adhesion loss was large in the small amount of the reaction operation of Example 1, and the yield was more accurate in a large amount of the reaction.
  • Example 2 The difference from Example 1 is that the molar ratio of methyl glycidyl ether b1 to a1 is 5:1, and the yield is 93%.
  • Example 2 The difference from Example 1 was that the molar ratio of methyl glycidyl ether b1 to a1 was 1:1, and the yield was 69%.
  • Example 2 The difference from Example 1 is that the molar ratio of methyl glycidyl ether b1 to a1 is 8:1, and the yield is 94%.
  • Example 2 The difference from Example 1 was that the Schlenck tube was heated in an oil bath at 80 ° C for 35 hours, and the product yield was 84%.
  • Example 2 The difference from Example 1 was that the above Schlenck tube was heated in a 100 ° C oil bath for 35 hours, and the product yield was 91%.
  • Example 2 The difference from Example 1 was that the Schlenck tube was heated in a 150 ° C oil bath for 35 hours, and the product yield was 82%.
  • Example 2 The difference from Example 1 was that the above Schlenck tube was heated in a 50 ° C oil bath for 35 hours, and the product yield was 48%.
  • Example 2 The difference from Example 1 was that the above Schlenck tube was heated in a 165 ° C oil bath for 35 hours, and the product yield was 74%.
  • Example 2 The difference from Example 1 was that the pH adjusting agent used was CF 3 CO 2 K, and the product yield was 93%.
  • Example 2 The difference from Example 1 was that the pH adjusting agent used was KHCO 3 and the product yield was 74%.
  • Example 2 The difference from Example 1 was that the pH adjusting agent used was K 2 HPO 4 and the product yield was 51%.
  • Example 2 The difference from Example 1 was that the pH adjusting agent used was K 2 CO 3 and the product yield was 22%.
  • A1 (87.5 mg, 0.2 mmol), NaHCO 3 (16.8 mg, 0.2 mmol), absolute ethanol (2.0 mL, water ⁇ 0.01 wt%), methyl group were sequentially added to a 25 mL dry clean Schlenck tube with a magnetic stir bar.
  • Glycidyl ether b1 (52.9 mg, 0.6 mmol) formed a reaction system.
  • the above Schlenck tube was placed in a 90 ° C oil bath and heated for 35 hours. TLC showed the starting material was completely reacted to give the product system. The product system was cooled to room temperature, and the solvent was evaporated to dryness.
  • A1 (86.8 mg, 0.2 mmol), potassium acetate (19.6 mg, 0.2 mmol), absolute ethanol (3.0 mL, water ⁇ 0.01 wt%), methyl group were sequentially added to a 25 mL dry clean Schlenck tube with a magnetic stir bar.
  • Glycidyl ether b1 (52.9 mg, 0.6 mmol) formed a reaction system.
  • the above Schlenck tube was placed in a 90 ° C oil bath and heated for 35 hours. TLC showed the starting material was completely reacted to give the product system. The product was quenched and cooled to room temperature, and the solvent was evaporated to dryness.
  • A1 (86.8 mg, 0.2 mmol), potassium acetate (19.6 mg, 0.2 mmol), absolute ethanol (4.0 mL, water ⁇ 0.01 wt%), methyl group were sequentially added to a 25 mL dry clean Schlenck tube with a magnetic stir bar.
  • Glycidyl ether b1 (52.9 mg, 0.6 mmol) formed a reaction system.
  • the above Schlenck tube was placed in a 90 ° C oil bath and heated for 35 hours. TLC showed the starting material was completely reacted to give the product system. The product was quenched and cooled to room temperature, and the solvent was evaporated to dryness.
  • Example 2 The difference from Example 1 was that the solvent used was methanol and the product yield was 91%.
  • Example 1 The difference from Example 1 was that the solvent used was isopropanol and the product yield was 95%.
  • Example 1 The difference from Example 1 was that the solvent used was isobutanol and the product yield was 92%.
  • Example 1 The difference from Example 1 was that the solvent used was isoamyl alcohol and the product yield was 87%.
  • Example 2 The difference from Example 1 was that the product system was stopped by heating to cool to room temperature, and the solvent was removed under reduced pressure to give a residue. To the residue was added 2.0 mL of purified water to form a mixture, and the mixture was adjusted to pH 3.5 with 3M hydrochloric acid. Then, the organic phase was extracted with n-hexane (3 mL ⁇ 3), and the combined organic phase was dried over anhydrous sodium sulfate, and dried and filtered, yield 91%.
  • the difference from the first embodiment is that the product system is stopped by heating to cool to room temperature, and the solvent is removed under reduced pressure to give a residue.
  • the residue 2.0 mL of purified water is added to form a mixture, and the mixture is adjusted to pH 4.5 with 3 M hydrochloric acid with stirring.
  • the organic phase was extracted with n-hexane (3 mL ⁇ 3), and the combined organic phase was dried over anhydrous sodium sulfate, and dried and filtered, yield 89%.
  • the difference from the first embodiment is that the product system is stopped by heating to cool to room temperature, and the solvent is removed under reduced pressure to obtain a residue.
  • the residue 2.0 mL of purified water is added to form a mixture, and the mixture is adjusted to pH 5 with 3 M hydrochloric acid with stirring.
  • the organic phase was extracted with n-hexane (3 mL ⁇ 3), and the combined organic phase was dried over anhydrous sodium sulfate, and dried and filtered, yield 84%.
  • Example 2 The difference from Example 1 was that the amide compound used was a2 in a yield of 96.
  • Example 2 The difference from Example 1 was that the amide compound used was a3 in a yield of 41%.
  • Example 2 The difference from Example 1 was that the amide compound used was a4 in a yield of 97%.
  • Example 2 The difference from Example 1 was that the amide compound used was a5 in a yield of 96%.
  • Example 2 The difference from Example 1 was that the amide compound used was a6 in a yield of 93%.
  • Example 2 The difference from Example 1 was that the amide compound used was a7 in a yield of 90%.
  • Example 2 The difference from Example 1 was that the amide compound used was a8 in a yield of 62%.
  • Example 2 The difference from Example 1 was that the amide compound used was a9 in a yield of 91%.
  • Example 2 The difference from Example 1 was that the amide compound used was a10 in a yield of 97%.
  • Example 2 The difference from Example 1 was that the amide compound used was a11 in a yield of 94%.
  • Example 2 The difference from Example 1 was that the amide compound used was a12 in a yield of 90%.
  • Example 2 The difference from Example 1 was that the amide compound used was 1 m in a yield of 89%.
  • each of the amide-containing compounds can be obtained by using a commercially available product in the prior art or by subjecting the corresponding substrate to CH activation.
  • the product system obtained by the activation of CH can be directly subjected to the amido alcoholysis of the following examples without purification.
  • A20 (143.53 mg, 0.2 mmol), potassium acetate (19.6 mg, 0.2 mmol), absolute ethanol (2.0 mL, water ⁇ 0.01 wt%), methyl group were sequentially added to a 25 mL dry clean Schlenck tube with a magnetic stir bar.
  • Glycidyl ether b1 (52.9 mg, 0.6 mmol) formed a reaction system.
  • the above Schlenck tube was placed in a 90 ° C oil bath and heated for 35 hours. TLC showed the starting material was completely reacted to give the product system. The product was quenched and cooled to room temperature, and the solvent was evaporated to dryness.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b2 in a yield of 92%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b3 in a yield of 69%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b4 in a yield of 21%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b5 in a yield of 68%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b6 in a yield of 87%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b7 in a yield of 89%.
  • Example 2 The difference from Example 1 was that the epoxy compound used was b8 in a yield of 47%.
  • the method provided by the present application not only is easy to operate, but also requires only a simple conventional separation step to obtain a pure product, and at the same time, since the cost of the epoxy compound is low, the production operation cost and the risk of the three waste treatment can be greatly reduced. And cost. Moreover, when the above method is used, the reaction conditions are mild, and it is compatible with various substituents and functional groups, and the amides of various structural types can be obtained with good yield, and the substrate has a wide application range. That is, the present invention provides an environmentally friendly, economical and efficient method for amide alcoholysis.
  • the above alcoholysis reaction of the present application is not affected by the impurities in the C-H activation reaction system of the previous step, and the intermediate purification step is saved, and the two-step reaction of C-H activation and amide alcoholysis can be continuously administered.

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Abstract

本发明提供了一种酰胺醇解的方法。该方法包括使用环氧化合物作为促进剂，在碱性条件下对含酰胺化合物进行醇解。上述方法不仅操作简便易行，而且后处理只需简单的常规分离步骤即可得到纯产物，同时由于环氧化合物成本低廉，因此可以大大降低了生产操作成本和三废处理的风险和成本。且上述方法在使用时，反应条件温和，能够兼容各种不同取代基和官能团，对各种不同结构类型的酰胺均能取得很好的收率，底物适用范围广。即本发明为酰胺转化为更有用的酯提供了一条环境友好，经济实用的高效方法。本申请的上述醇解反应不会受到上一步C-H活化反应体系中的杂质影响，节省中间体纯化步骤，可以C-H活化和酰胺醇解两步反应连投。

Description

一种酰胺醇解的方法 技术领域
本发明涉及有机材料合成领域，具体而言，涉及一种酰胺醇解的方法。
背景技术
酰胺键作为一种常见官能团，广泛存在于蛋白质等天然产物和合成化合物中。人们通常认为酰胺键的共振稳定性使酰胺成为一种较弱的亲电试剂(The structure of proteins:two hydrogenbonded helical configurations of the polypeptide chain.Proc.Natl.Acad.Sci.1951,37,205)，以至很难用化学合成的方法选择性的打开酰胺的C-N键(Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds.Nature 2015,524,79)。
-CONHArF(ArF＝p-CF3C6F4)作为一种优异的酰胺导向基，在各种不同类型的β-C–H活化反应中具有十分广泛的应用，但其缺点是对于某些底物来说，该导向基很难脱除4(Ligand-Enabledβ-C-H Arylation ofα-Amino Acids Using a Simple and Practical Auxiliary.J.Am.Chem.Soc.2015,137,3338)。这大大限制了这些C–H活化产物的进一步转化利用，所以有必要发展一种普适的脱除该导向基的方法。
已有的脱除该导向基的方法：1.在强碱水溶液中加热，使酰胺水解成羧酸；2.在强酸中加热，使酰胺水解成羧酸；3.加入NaNO2在Ac2O/AcOH混合溶剂中得到羧酸；4.使用BF3·Et2O在甲醇中加热得到；5.LiHMDS/MeOCOCl/MeONa分步反应实现水解成酯。
上述使用BF3·Et2O在100℃下反应，实现导向基的醇解，该方法具有试剂价格较贵，操作复杂，反应条件苛刻的缺点。上述其余方法需要强酸或强碱条件，许多官能团在此条件下并不稳定。且以上方法均受底物位阻影响明显，底物适用范围小。
发明内容
本发明的主要目的在于提供一种酰胺醇解的方法，以解决现有技术中的酰胺醇解方法操作复杂、反应条件苛刻的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种酰胺醇解的方法，该方法包括使用环氧化合物作为醇解促进剂，在碱性条件下对含酰胺化合物进行醇解。
进一步地，以环氧化合物和酰胺化合物的摩尔比计，上述环氧化合物和酰胺化合物的用量比为1～5：1。
进一步地，上述含酰胺化合物具有通式I，通式I为
Figure PCTCN2017083498-appb-000001
R1，R2各自独立地选自烷基、芳基、取代烷基和取代芳基中的任意一种，优选烷基选自C1～C18的烷基中的任意一种，优选取代烷基的主链碳原子数为C1～C18中的任意一种，优选取代烷基为单取代烷基或多取代烷基，优选取代烷基中的取代基选自芳基、芳香杂环取代基、环烷烃、杂环烷烃、烯基和炔基中的任意一种或多种的组合取代基。
进一步地，上述环氧化合物具有通式II，通式II为
Figure PCTCN2017083498-appb-000002
R3和R4各自独立地选自H、烷基和芳基中的任一种，优选烷基选自C1～C18的烷基中的任意一种。
进一步地，上述方法包括：将含酰胺化合物、环氧化合物、pH值调节剂和溶剂混合，形成碱性反应体系，优选碱性反应体系的pH值为7.5～9.5；使碱性反应体系在50～150℃下反应以对含酰胺化合物进行醇解。
进一步地，上述pH值调节剂为弱酸或弱碱，优选pH值调节剂选自CF3CO2K、CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、LiHCO3、CsF、KF、NaF、LiF、Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、Na3PO4、苯甲酸钠、四甲基乙二胺、N-N二异丙基乙胺和三乙胺中的任意一种或多种。
进一步地，上述溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、异戊醇、乙二醇、丙三醇、1,2-二甲氧基乙烷、乙二醇二乙醚、2-甲氧基乙基醚、2-乙氧基乙基醚和吡咯中的任意一种或多种。
进一步地，上述含酰胺化合物为
Figure PCTCN2017083498-appb-000003
环氧化合物为甲基缩水甘油醚，pH值调节剂为KOAc，溶剂为乙醇。
进一步地，上述碱性反应体系在80～100℃下反应以对含酰胺化合物进行醇解。
进一步地，在醇解完成后，上述方法还包括：对醇解产物进行减压去溶剂，得到残留物；将残留物与水混合形成混合物；调节混合物的pH值至3.5～4.5后采用正己烷进行萃取，得到有机相；以及对有机相进行干燥、过滤。
进一步地，在醇解完成后，上述方法还包括：对醇解产物进行减压去溶剂，得到残留物；采用硅胶柱层析对残留物进行纯化。
应用本发明的技术方案，上述方法不仅操作简便易行，而且后处理只需简单的常规分离步骤即可得到纯产物，同时由于环氧化合物成本低廉，因此可以大大降低了生产操作成本和三废处理的风险和成本。且上述方法在使用时，反应条件温和，能够兼容各种不同取代基和 官能团，对各种不同结构类型的酰胺均能取得很好的收率，底物适用范围广。即本发明为酰胺-的醇解提供了一条环境友好，经济实用的高效方法。本申请的上述醇解反应不会受到上一步C-H活化反应体系中的杂质影响，节省中间体纯化步骤，可以C-H活化和酰胺基醇解两步反应连投。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如本申请背景技术所分析的，现有技术中虽然有多种酰胺-醇解的方法，但是，上述各方法均具有不同的缺陷，比如使用BF3·Et2O在100℃下反应实现酰胺的醇解时，该方法具有试剂价格较贵，操作复杂，反应条件苛刻的缺点，为了解决该问题，本申请提供了一种酰胺醇解的方法，该方法包括使用环氧化合物作为促进剂，在碱性条件下对含酰胺化合物进行醇解。
本申请发明人在对酰胺化合物进行导向基脱除的研究时，意外发现，在碱性条件下使用环氧化合物的醇溶液可以促进酰胺转化为酯，具有一定酸性的酰胺N-H在碱性条件下亲核进攻被活化的环氧烷开环，形成N-加成的过渡态产物，该过渡态不稳定，在环氧烷开环后原位生成的氧负离子亲核进攻酰胺键的羰基后，酰胺基团的C-N键断开，完成酰胺醇解反应。
上述方法不仅操作简便易行，而且后处理只需简单的常规分离步骤即可得到纯产物，同时由于环氧化合物成本低廉，因此可以大大降低了生产操作成本和三废处理的风险和成本。且上述方法在使用时，反应条件温和，能够兼容各种不同取代基和官能团，对各种不同结构类型的酰胺均能取得很好的收率，底物适用范围广。即本发明为酰胺的醇解提供了一条环境友好，经济实用的高效方法。本申请的上述醇解反应不会受到上一步C-H活化反应体系中的杂质影响，节省中间体纯化步骤，可以C-H活化和酰胺醇解两步反应连投。
为了尽可能提高酰胺的转换率且保证环氧化合物的利用率，优选以环氧化合物和酰胺化合物的摩尔比计，环氧化合物和含酰胺化合物的用量比为1～5：1。当然，当环氧化合物和含酰胺化合物的用量比大于5:1时，也能实现醇解，只不过会有较多的环氧化合物没有参与反应，造成原料的浪费。
本申请的方法反应底物普适性广，受位阻作用影响不明显，几乎所有结构的酰胺底物均能顺利反应取得很好的收率，优选该含酰胺化合物具有通式I，该通式I为
Figure PCTCN2017083498-appb-000004
R1，R2各自独立地选自烷基、芳基、取代烷基和取代芳基中的任意一种，优选烷基选自C1～C18的烷基中的任意一种，优选取代烷基的主链碳原子数为C1～C18中的任意一种，优选取代烷基为单取代烷基或多取代烷基，优选取代烷基中的取代基选自芳基、芳香杂环取代基、环烷烃、杂环烷烃、烯基和炔基中的任意一种或多种的组合取代基，上述取代芳基中的取代基可以为卤 素、烷基、取代烷基等，比如R2为
Figure PCTCN2017083498-appb-000005
具有上述通式结构的含酰胺化合物的反应过程所需的反应温度更温和、反应时间也较短，更适合工业化大规模应用。
为了进一步降低上述方法的实施成本，优选上述环氧化合物具有通式II，该通式II为
Figure PCTCN2017083498-appb-000006
R3和R4各自独立地选自H、烷基和芳基中的任一种，优选上述烷基选自C1～C18的烷基中的任意一种。
上述利用环氧化合物作为促进剂进行醇解时，其具体的实施过程可以参考现有技术中醇解过程，优选上述方法包括：将含酰胺化合物、环氧化合物、pH值调节剂和溶剂混合，形成碱性反应体系；使碱性反应体系在50～150℃下反应以对含酰胺化合物进行醇解。优选该碱性反应体系的pH值为7.5～9.5。
将含酰胺化合物、环氧化合物在溶剂中分散后，利用pH值调节剂调节碱性反应体系以使后续的醇解顺利、高效进行，尤其是当碱性反应体系的pH值为7.5～9.5时，反应速率更为理想；然后反应体系在50～150℃的低温条件下即可进行。由上述过程可见，本申请的方法不需要特殊的昂贵试剂、反应条件温和，且适用的底物较广，适用范围较大。
上述pH所需的pH值调节剂不需要强酸和强碱，优选为弱酸或弱碱，进一步优选pH值调节剂选自CF3CO2K、CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、LiHCO3、CsF、KF、NaF、LiF、Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、Na3PO4、苯甲酸钠、四甲基乙二胺、N-N二异丙基乙胺和三乙胺中的任意一种或多种。上述各物质成本低廉且形成的pH体系温和。
本申请的溶剂可以参考现有技术中酰胺醇解常用的溶剂种类，优选上述溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、异戊醇、乙二醇、丙三醇、1,2-二甲氧基乙烷、乙二醇二乙醚、2-甲氧基乙基醚、2-乙氧基乙基醚和吡咯中的任意一种或多种。
以下以KOAc为pH值调节剂，以乙醇为溶剂为例进一步说明上述反应原理：具有一定酸性的酰胺N-H在KOAc作用下亲核进攻钾离子活化过的环氧烷开环，形成N-加成的过渡态产物，该过渡态不稳定，在环氧烷开环后原位生成的氧负离子亲核进攻酰胺键的羰基后，酰胺基团的C-N键断开，形成酯化中间体产物，然后酯化中间体和醇类溶剂发生酯交换反应，生成最终酰胺醇解产物。具体可参见以下化学反应过程：
Figure PCTCN2017083498-appb-000007
在本申请一种优选的实施例中，上述含酰胺化合物为
Figure PCTCN2017083498-appb-000008
环氧化合物为甲基缩水甘油醚，pH值调节剂为KOAc，溶剂为乙醇。
当本申请的方法应用至上述含酰胺化合物的醇解中时，最终目标产物的收率较高。
为了进一步加快反应速率，提高收率，优选上述碱性反应体系在80～100℃下反应以对含酰胺化合物进行醇解。
为了减少反应消耗成本，优选采用油浴对反应体系进行加热。
在上述醇解完成后，优选上述方法还包括：对醇解产物进行减压去溶剂，得到残留物；将残留物与水混合形成混合物；调节混合物的pH值至3.5～4.5后采用正己烷进行萃取，得到有机相；以及对有机相进行干燥、过滤。上述过程所采用的各物质均为常规材料，因此不会增加本申请方法实施的成本；而且，上述过程为纯化过程中的常规操作，也不会增加本申请方法的复杂性；进一步地，在萃取时，将混合物的pH值控制在3.5～4.5之间，有利于提高萃取分离效率，比如调pH值为酸性，使离去基团上的仲胺结构成盐，增强离去基团的水溶性，使离去基团副产物更容易水洗除去。若酸性更强可能会使产物上的其他官能团变质，同时造成试剂浪费。或者，在上述醇解完成后，优选上述方法还包括：对醇解产物进行减压去溶剂，得到残留物；采用硅胶柱层析对残留物进行纯化，该过程适合实验室小批量试验的产物分离。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
以下各实施例中所采用的，含酰胺化合物如下：
Figure PCTCN2017083498-appb-000009
环氧化合物如下：
Figure PCTCN2017083498-appb-000010
产物结构如下：
Figure PCTCN2017083498-appb-000011
以下各实施例采用的反应物如下表：
  酰胺化合物 环氧化合物 pH值调节剂 溶剂
实施例1至2 a1 b1 KOAc 无水乙醇
实施例3至10 a1 b1 KOAc 无水乙醇
实施例11 a1 b1 CF3CO2K 无水乙醇
实施例12 a1 b1 KHCO3 无水乙醇
实施例13 a1 b1 K2HPO4 无水乙醇
实施例14 a1 b1 K2CO3 无水乙醇
实施例15 a1 b1 NaHCO3 无水乙醇
实施例16 a1 b1 LiOH 无水乙醇
实施例17 a1 b1 NaOAc 无水乙醇
实施例18 a1 b1 KCl 无水乙醇
实施例19 a1 b1 CF3COONa 无水乙醇
实施例20 a1 b1 CF3COOK 无水乙醇
实施例21 a1 b1 三乙胺 无水乙醇
实施例22 a1 b1 KOAc 无水乙醇
实施例23 a1 b1 KOAc 无水乙醇
实施例24 a1 b1 KOAc 无水乙醇
实施例25 a1 b1 KOAc 甲醇
实施例26 a1 b1 KOAc 异丙醇
实施例27 a1 b1 KOAc 异丁醇
实施例28 a1 b1 KOAc 异戊醇
实施例29 a1 b1 KOAc 无水乙醇
实施例30 a1 b1 KOAc 无水乙醇
实施例31 a1 b1 KOAc 无水乙醇
实施例32 a2 b1 KOAc 无水乙醇
实施例33 a3 b1 KOAc 无水乙醇
实施例34 a4 b1 KOAc 无水乙醇
实施例35 a5 b1 KOAc 无水乙醇
实施例36 a6 b1 KOAc 无水乙醇
实施例37 a7 b1 KOAc 无水乙醇
实施例38 a8 b1 KOAc 无水乙醇
实施例39 a9 b1 KOAc 无水乙醇
实施例40 a10 b1 KOAc 无水乙醇
实施例41 a11 b1 KOAc 无水乙醇
实施例42 a12 b1 KOAc 无水乙醇
实施例43 a13 b1 KOAc 无水乙醇
实施例44 a14 b1 KOAc 无水乙醇
实施例45 a15 b1 KOAc 无水乙醇
实施例46 a16 b1 KOAc 无水乙醇
实施例47 a17 b1 KOAc 无水乙醇
实施例48 a18 b1 KOAc 无水乙醇
实施例49 a19 b1 KOAc 无水乙醇
实施例50 a20 b1 KOAc 无水乙醇
实施例51 a21 b1 KOAc 无水乙醇
实施例52 a22 b1 KOAc 无水乙醇
实施例53 a23 b1 KOAc 无水乙醇
实施例54 a24 b1 KOAc 无水乙醇
实施例55 a25 b1 KOAc 无水乙醇
实施例56 a26 b1 KOAc 无水乙醇
实施例57 a27 b1 KOAc 无水乙醇
实施例58 a28 b1 KOAc 无水乙醇
实施例59 a29 b1 KOAc 无水乙醇
实施例60 a1 b2 KOAc 无水乙醇
实施例61 a1 b3 KOAc 无水乙醇
实施例62 a1 b4 KOAc 无水乙醇
实施例63 a1 b5 KOAc 无水乙醇
实施例64 a1 b6 KOAc 无水乙醇
实施例65 a1 b7 KOAc 无水乙醇
实施例66 a1 b8 KOAc 无水乙醇
实施例1
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(87.5mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水<0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，向残留物中加入2.0mL纯化水形成混合物，并搅拌下用3M盐酸调混合物的pH为4，然后用正己烷(3mL×3)萃取得到有机相，对合并后的有机相采用无水硫酸钠进行干燥，干燥完成后过滤，滤液浓缩后得纯的产物45.5mg，收率92％。
上述醇解过程的化学反应见下式：
Figure PCTCN2017083498-appb-000012
产物c1(Ethyl 2-(1,3-dioxoisoindolin-2-yl)propanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.92–7.79(m,2H),7.77–7.60(m,2H),4.95(q,J＝7.5Hz,1H),4.19(td,J＝7.0,3.5Hz,2H),1.69(d,J＝7.5Hz,3H),1.22(t,J＝7.0Hz,3H)。13C NMR(125MHz,CDCl3)δ169.75,167.47,134.20,131.99,123.49,61.90,47.66,15.28,14.12.
实施例2
与实施例1的区别在于，将实施例1的各物料的用量扩大100倍后，采用500mL压力反应釜进行醇解反应，滤液浓缩后得纯的产物4.648g，收率94％，实施例2的收率大于实施例1的收率，是由于实施例1小量反应操作时粘附损失大，大量反应时收率更准确。
实施例3
与实施例1的区别在于，其中甲基缩水甘油醚b1和a1的摩尔比为5:1，收率93％。
实施例4
与实施例1的区别在于，其中甲基缩水甘油醚b1和a1的摩尔比为1:1，收率69％。
实施例5
与实施例1的区别在于，其中甲基缩水甘油醚b1和a1的摩尔比为8:1，收率94％。
实施例6
与实施例1的区别在于，将上述Schlenck管置于80℃油浴中加热反应35小时，产物收率为84％。
实施例7
与实施例1的区别在于，将上述Schlenck管置于100℃油浴中加热反应35小时，产物收率为91％。
实施例8
与实施例1的区别在于，将上述Schlenck管置于150℃油浴中加热反应35小时，产物收率为82％。
实施例9
与实施例1的区别在于，将上述Schlenck管置于50℃油浴中加热反应35小时，产物收率为48％。
实施例10
与实施例1的区别在于，将上述Schlenck管置于165℃油浴中加热反应35小时，产物收率为74％。
实施例11
与实施例1的区别在于，所采用的pH值调节剂为CF3CO2K，产物收率为93％。
实施例12
与实施例1的区别在于，所采用的pH值调节剂为KHCO3，产物收率为74％。
实施例13
与实施例1的区别在于，所采用的pH值调节剂为K2HPO4，产物收率为51％。
实施例14
与实施例1的区别在于，所采用的pH值调节剂为K2CO3，产物收率为22％。
实施例15
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(87.5mg,0.2mmol)、NaHCO3(16.8mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物36.1mg，收率73％。
实施例16
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、LiOH(4.8mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物32.1mg，收率65％。本实施例采用的pH值调节剂采用的LiOH，该物质为强碱，在反应中不仅起到了调节pH值的作用，也可能作为金属离子起络合活化作用。
实施例17
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、NaOAc(16.4mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物43.0mg，收率87％。
实施例18
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、KCl(14.9mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物15.3mg，收率31％。
实施例19
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、三氟乙酸钠(27.2mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应45小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物46.0mg，收率93％。
实施例20
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、三氟乙酸钾(30.4mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应45小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物47.0mg，收率95％。虽产率稍有提高，但反应时间延长，同时三氟乙酸钾和醋酸钾相比成本更高。
实施例21
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、三乙胺(20.2mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物35.6mg，收率72％。
实施例22
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(1.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物38.6mg，收率78％。
实施例23
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(3.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物44.0mg，收率89％。
实施例24
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a1(86.8mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(4.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物20.3mg，收率41％。
实施例25
与实施例1的区别在于，采用的溶剂为甲醇，产物收率为91％。
产物c2(Methyl 2-(1,3-dioxoisoindolin-2-yl)propanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.82–7.75(m,2H),7.72–7.65(m,2H),4.91(q,J＝7.5Hz,1H),3.67(s,3H),1.63(d,J＝7.5Hz,3H).
实施例26
与实施例1的区别在于，采用的溶剂为异丙醇，产物收率为95％。
产物c3(Isopropyl 2-(1,3-dioxoisoindolin-2-yl)propanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.83–7.76(m,2H),7.72–7.66(m,2H),5.09–4.95(m,1H),4.87(q,J＝7.5Hz,1H),1.63(d,J＝7.5Hz,1H),1.16(dd,J＝20.0,6.5Hz,6H).
实施例27
与实施例1的区别在于，采用的溶剂为异丁醇，产物收率为92％。
产物c4(Isobutyl 2-(1,3-dioxoisoindolin-2-yl)propanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.83–7.76(m,2H),7.73–7.65(m,2H),4.94(q,J＝7.5Hz,1H),3.93–3.83(m,2H),1.90–1.77(m,1H),1.67(d,J＝7.5Hz,3H),0.81(d,J＝7.0Hz,6H).
实施例28
与实施例1的区别在于，采用的溶剂为异戊醇，产物收率为87％。
产物c5(Isopentyl 2-(1,3-dioxoisoindolin-2-yl)propanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.85–7.80(m,2H),7.74–7.67(m,2H),4.98–4.89(m,1H),4.14(t,J＝7.0Hz,2H),1.67(d,J＝7.5Hz,3H),1.59–7.50(m,1H),1.49–1.37(m,2H),0.84–0.75(m,6H).
实施例29
与实施例1的区别在于，将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，向残留物中加入2.0mL纯化水形成混合物，并搅拌下用3M盐酸调混合物的pH为3.5，然后用正己烷(3mL×3)萃取得到有机相，对合并后的有机相采用无水硫酸钠进行干燥，干燥完成后过滤，收率91％。
实施例30
与实施例1的区别在于，将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，向残留物中加入2.0mL纯化水形成混合物，并搅拌下用3M盐酸调混合物的pH为4.5，然后用正己烷(3mL×3)萃取得到有机相，对合并后的有机相采用无水硫酸钠进行干燥，干燥完成后过滤，收率89％。
实施例31
与实施例1的区别在于，将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，向残留物中加入2.0mL纯化水形成混合物，并搅拌下用3M盐酸调混合物的pH为5，然后用正己烷(3mL×3)萃取得到有机相，对合并后的有机相采用无水硫酸钠进行干燥，干燥完成后过滤，收率84％。
实施例32
与实施例1的区别在于，采用的酰胺化合物为a2，收率为96。
产物c6(Ethyl 3-phenylpropanoate)的核磁测试结果：
a8NMR(500MHz,CDCl3)δ7.32–7.26(m,2H),7.24–7.17(m,3H),4.13(q,J＝7.0Hz,2H),2.96(t,J＝8.0Hz,2H),2.63(t,J＝8.0Hz,2H),1.24(t,J＝7.0Hz,3H)。
实施例33
与实施例1的区别在于，采用的酰胺化合物为a3，收率为41％。
实施例34
与实施例1的区别在于，采用的酰胺化合物为a4，收率为97％。
实施例35
与实施例1的区别在于，采用的酰胺化合物为a5，收率为96％。
实施例36
与实施例1的区别在于，采用的酰胺化合物为a6，收率为93％。
实施例37
与实施例1的区别在于，采用的酰胺化合物为a7，收率为90％。
实施例38
与实施例1的区别在于，采用的酰胺化合物为a8，收率为62％。
产物c7(Ethyl benzoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ8.13–7.97(m,2H),7.58–7.53(m,1H),7.47–7.38(m,2H),4.39(q,J＝7.0Hz,2H),1.42(t,J＝7.0Hz,3H)。
实施例39
与实施例1的区别在于，采用的酰胺化合物为a9，收率为91％。
产物c8(Ethyl 2-methyl-3-phenylacrylate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.70(s,1H),7.43–7.36(m,4H),7.35–7.29(m,1H),4.28(q,J＝7.0Hz,2H),2.13(s,3H),1.36(t,J＝7.0Hz,3H).
实施例40
与实施例1的区别在于，采用的酰胺化合物为a10，收率为97％。
实施例41
与实施例1的区别在于，采用的酰胺化合物为a11，收率为94％。
产物c9(Ethyl 2,2-dimethyl-3-phenylpropanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.30–7.27(m,2H),7.25–7.20(m,a8),7.13(d,J＝7.0Hz,2H),4.13(q,J＝7.0Hz,2H),2.87(s,2H),1.25(t,J＝7.0Hz,4H),1.19(s,6H).13C NMR(125MHz,CDCl3)δ177.62,138.10,130.30,128.06,126.52,60.52,46.41,43.61,25.09,14.31。
实施例42
与实施例1的区别在于，采用的酰胺化合物为a12，收率为90％。
产物c10(Ethyl 2,2-dimethyl-3-phenylpropanoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.85–7.75(m,2H),7.74–7.67(m,2H),4.22(q,J＝7.0Hz,2H),1.83(s,6H),1.25(t,J＝7.0Hz,3H)。
实施例43
与实施例1的区别在于，采用的酰胺化合物为1m，收率为89％。
产物c11(Ethyl 1-benzoylpyrrolidine-2-carboxylate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.55(d,J＝6.5Hz,2H),7.43–7.35(m,3H),4.69–4.59(m,1H),4.22(q,J＝7.0Hz,2H),3.64(dt,J＝14.0,7.0Hz,1H),3.56–3.47(m,1H),2.31(dd,J＝14.0,7.0Hz,1H),2.04–1.97(m,2H),1.92–1.82(m,1H),1.29(t,J＝7.0Hz,3H)。
以下实施例44至59的结构式中的ArF为p-CF3C5F4，且各含酰胺化合物可以采用现有技术中已有的商品或者对相应的底物进行C-H活化得到，同时也可利用C-H活化后得到的产物体系不需要进行提纯直接可进行以下各实施例的酰胺基醇解。
实施例44
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a14(87.06mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水甲醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC 显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物42.3mg，收率90％。
产物c12(Methyl 4-(2-(methoxycarbonyl)cyclopropyl)benzoate)的核磁测试结果：
1NMR(400MHz,CDCl3)δ7.94(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),3.89(s,3H),3.43(s,3H),2.60(q,J＝8.0Hz,1H),2.18–2.13(m,1H),1.77–1.72(m,1H),1.43–1.37(m,1H)。
实施例45
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a15(89.86mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水甲醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物，收率93％。
产物c13(Methyl 4-(2-(methoxycarbonyl)cyclobutyl)benzoate)的核磁测试结果：
1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),3.91(s,3H),3.88–3.81(m,1H),3.71(s,3H),3.22(q,J＝8.0Hz,1H),2.38–2.31(m,2H),2.29–2.12(m,2H).13C NMR(125MHz,CDCl3)δ174.66,167.13,148.93,129.86,128.39,126.50,52.16,51.94,45.07,43.10,25.33,21.90。
实施例46
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a16(105.08mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水甲醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物，收率95％。
产物c14(Dimethyl 4,4'-(2-(methoxycarbonyl)cyclobutane-1,3-diyl)dibenzoate)的核磁测试结果：
1H NMR(400MHz,CDCl3)δ8.00(d,J＝8.0Hz,4H),7.34(d,J＝8.0Hz,4H),3.91(s,6H),3.84(q,J＝8.0Hz,2H),3.75(s,3H),3.32–3.28(m,1H),2.87–2.81(m,1H),2.34–2.26(m,1H).13C NMR(125MHz,CDCl3)δ173.61,167.04,147.96,130.01,128.73,126.67,52.26,52.23,51.98,39.53,32.49,29.85。
实施例47
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a17(95.47mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC 显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物53.8mg，收率93％。
产物c15(Ethyl 4-(2-(ethoxycarbonyl)cyclopentyl)benzoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.96(t,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),4.35(q,J＝7.0Hz,2H),4.05(q,J＝7.0Hz,2H),3.37(q,J＝9.0Hz,1H),2.81(q,J＝9.0Hz,1H),2.24–2.10(m,2H),2.02–1.93(m,1H),1.91–1.79(m,2H),1.79–1.69(m,1H),1.37(t,J＝7.0Hz,3H),1.14(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ175.54,166.67,149.47,129.83,128.74,127.34,60.90,60.50,52.18,49.86,35.08,30.84,25.16,14.47,14.31。
实施例48
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a18(98.28mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物54.1mg，收率89％。
产物c16(Ethyl 4-(2-(ethoxycarbonyl)cyclohexyl)benzoate的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.94(d,J＝8.0Hz,2H),7.26(d,J＝8.0Hz,2H),4.35(q,J＝7.0Hz,2H),3.90–3.80(m,2H),2.89–2.76(m,1H),2.63–2.53(m,1H),2.08–1.99(m,1H),1.92–1.78(m,3H),1.62–1.56(m,1H),1.50–1.42(m,2H),1.42–1.34(m,4H),0.94(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ174.95,166.72,150.21,129.75,128.74,127.49,60.90,60.09,49.97,46.82,34.18,30.17,26.19,25.42,14.47,14.10.
实施例49
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a19(113.90mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝25/1)，得纯的产物，收率95％。
产物c17(Ethyl 4-(3-ethoxy-2-(4-isobutylphenyl)-3-oxopropyl)benzoate)的核磁测试结果：
1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.0Hz,2H),7.21–7.17(m,4H),7.08(d,J＝8.0Hz,2H),4.35(q,J＝8.0Hz,2H),4.15–3.96(m,2H),3.83–3.76(m,1H),3.46–3.41(m,1H),3.08–3.03(m,1H),2.44(d,J＝8.0Hz,2H),1.89–1.79(m,1H),1.38(t,J＝8.0Hz,3H),1.12(t,J＝8.0Hz,3H),0.89(d,J＝8.0Hz,6H).13C NMR(125MHz,CDCl3)δ173.30,166.65,144.65,141.00,135.66,129.63,129.47,129.08,128.70,127.65,60.91,53.05,45.11,39.95,30.26,22.44,14.42,14.14。
实施例50
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a20(143.53mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝25/1)，得纯的产物，收率96％。
产物c18(Diethyl 4,4'-(3-ethoxy-2-(4-isobutylphenyl)-3-oxopropane-1,1-diyl)dibenzoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),6.94(d,J＝8.0Hz,2H),4.79(d,J＝12.0Hz,1H),4.40–4.33(m,3H),4.27(q,J＝7.0Hz,2H),4.02–3.96(m,1H),3.94–3.88(m,1H),2.35(d,J＝7.0Hz,2H),1.79–1.73(m,1H),1.37(t,J＝7.0Hz,3H),1.31(t,J＝7.0Hz,3H),1.01(t,J＝7.0Hz,3H),0.82–0.80(m,6H)。
实施例51
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a21(99.49mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝50/1)，得纯的产物，收率96％。
产物c19(Ehyl 2-(5-isobutylbiphenyl-2-yl)propanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.47–7.40(m,2H),7.36(m,4H),7.15(d,J＝8.0Hz,1H),7.04(s,1H),4.17–4.05(m,2H),3.87(q,J＝7.0Hz,1H),2.49(d,J＝7.0Hz,2H),1.94–1.86(m,1H),1.37(d,J＝7.0Hz,3H),1.20(t,J＝7.0Hz,3H),0.94(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3)δ175.21,141.65,141.51,140.05,136.04,130.96,129.59,128.68,128.16,127.04,126.62,60.63,45.12,41.02,30.23,22.57,22.55,19.39,14.20。
实施例52
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a22(104.88mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物，收率93％。
产物c20(Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-p-tolylpropanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.82–7.74(m,2H),7.71–7.63(m,2H),7.04(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),5.15–5.08(m,1H),4.27–4.20(m,2H),3.58–3.46(m,2H),2.22(s,3H),1.25(t,J＝7.0Hz,3H)。
实施例53
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a23(82.46mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝15/1)，得纯的产物，收率94％。
产物c21(Ethyl 2-((2-fluoropyridin-4-yl)methyl)butanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ8.09(d,J＝5.0Hz,1H),6.99(d,J＝5.0Hz,1H),6.74(s,1H),4.15–4.01(m,2H),2.96(dd,J＝14.0,9.5Hz,1H),2.77(dd,J＝14.0,6.0Hz,1H),2.65–2.55(m,1H),1.72–1.65(m,1H),1.63–1.53(m,1H),1.16(t,J＝7.0Hz,3H),0.94(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)δ174.66,164.15(d,J＝237.5Hz,1H),154.76(d,J＝7.5Hz,1H),147.57(d,J＝15.0Hz,1H),122.07(d,J＝3.8Hz,1H),109.75(d,J＝36.3Hz,1H),60.65,48.01,37.14(d,J＝2.5Hz,1H),25.63,14.33,11.66.19F NMR(400MHz,CDCl3)δ-69.29(S)。
实施例54
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a24(120.10mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝20/1)，得纯的产物62.3mg，收率75％。
产物c22(Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-phenyl-3-p-tolylpropanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.83–7.69(m,2H),7.69–7.62(m,2H),7.50(d,J＝7.5Hz,1H),7.41(d,J＝7.5Hz,1H),7.33(t,J＝7.5Hz,1H),7.27(d,J＝9.0Hz,1H),7.22(t,J＝7.5Hz,0.5H),7.17(t,J＝7.0Hz,1H),7.11(t,J＝7.5Hz,1H),6.99(t,J＝7.5Hz,0.5H),6.93(d,J＝7.5Hz,1H),5.78–5.71(m,1H),5.33–5.23(m,1H),4.13–3.98(m,2H),2.32(s,1.5H),2.13(s,1.5H),1.06–0.98(m,3H).13C NMR(125MHz,CDCl3)δ168.43,168.37,167.49,167.44,142.03,140.84,138.75,137.61,136.46,136.44,134.11,131.52,131.45,129.47,129.32,128.73,128.57,127.98,127.83,127.81,127.70,126.85,123.50,123.45,77.41,77.16,76.91,61.75,61.71,55.40,55.26,50.33,50.29,29.81,21.14,20.99,13.83。
实施例55
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a25(118.89mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC 显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝10/1)，得纯的产物，收率91％。
产物c23(Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)-2-(ethoxycarbonyl)cyclopropyl)benzoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ8.02(d,J＝8.0Hz,2H),7.92–7.91(m,2H),7.79–7.77(m,2H),7.68(d,J＝8.0Hz,2H),4.38(q,J＝7.0Hz,1H),3.84–3.76(m,2H),3.17(t,J＝9.5Hz,1H),2.51(dd,J1＝6.5Hz,J2＝9.0Hz,1H),1.94(dd,J1＝6.5Hz,J2＝9.0Hz,1H),1.40(t,J＝7.0Hz,3H),0.78(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ168.22,167.65,166.66,140.20,134.56,131.87,129.91,129.46,123.76,61.74,61.07,38.21,33.48,19.24,14.50,13.84。
实施例56
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a26(107.64mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝20/1)，得纯的产物，收率89％。
产物c24(Ethyl 1-benzoyl-4-p-tolylpiperidine-3-carboxylate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.51–7.33(m,5H),7.18–7.01(m,2H),5.12–4.77(m,1H),4.08–3.70(m,3H),3.37–3.08(m,1H),3.04–2.55(m,3H),2.31(s,3H),1.89–1.60(m,2H),1.00–0.84(m,3H).
实施例57
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a27(78.26mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝30/1)，得纯的产物38.7mg，收率95％。
产物c25(Ethyl 2-methyl-3-phenylbut-2-enoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.42–7.35(m,2H),7.32–7.28(m,1H),7.17(d,J＝7.0Hz,2H),4.34–4.24(m,2H),2.28(d,J＝1.5Hz,3H),1.78(d,J＝1.5Hz,3H),1.38(t,J＝7.0Hz,3H).
实施例58
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a28(122.93mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC 显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝20/1)，得纯的产物，收率85％。
产物c26(Ethyl 2-(1,3-dioxoisoindolin-2-yl)-5-(triisopropylsilyl)pent-4-ynoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.88–7.81(m,2H),7.76–7.69(m,2H),5.08(dd,J＝12.0,5.0Hz,1H),4.29–4.15(m,2H),3.36(dd,J＝17.5,12.0Hz,1H),3.11(dd,J＝17.5,5.0Hz,1H),1.23(t,J＝7.0Hz,3H),0.88–0.76(m,21H).13C NMR(125MHz,CDCl3)δ168.05,167.31,134.21,132.02,123.59,102.79,83.66,62.28,50.91,20.86,18.43,18.42,14.19,11.11。
实施例59
向带有磁力搅拌子的25mL干燥洁净Schlenck管中依次加入a29(120.34mg,0.2mmol)、醋酸钾(19.6mg,0.2mmol)、无水乙醇(2.0mL，含水≤0.01wt％)、甲基缩水甘油醚b1(52.9mg,0.6mmol)，形成反应体系。将上述Schlenck管置于90℃油浴中加热反应35小时，TLC显示原料反应完全，得到产物体系。将产物体系停止加热冷至室温，并减压除去溶剂得到残留物，残留物经硅胶柱层析纯化(hexane/EA＝50/1)，得纯的产物，收率93％。
产物c27(Ethyl 2-(4-isobutyl-2-((triisopropylsilyl)ethynyl)phenyl)propanoate)的核磁测试结果：
1H NMR(500MHz,CDCl3)δ7.27–7.25(m,1H),7.21(d,J＝8.0Hz,1H),7.11–7.04(m,1H),4.37(q,J＝7.0Hz,1H),4.21–4.03(m,2H),2.41(d,J＝7.0Hz,2H),1.85(dp,J＝14.0,7.0Hz,1H),1.47(d,J＝7.0Hz,3H),1.20(t,J＝7.0Hz,3H),1.14(s,18H),0.90(d,J＝7.0Hz,6H)。
实施例60
与实施例1的区别在于，采用的环氧化合物为b2，收率为92％。
实施例61
与实施例1的区别在于，采用的环氧化合物为b3，收率为69％。
实施例62
与实施例1的区别在于，采用的环氧化合物为b4，收率为21％。
实施例63
与实施例1的区别在于，采用的环氧化合物为b5，收率为68％。
实施例64
与实施例1的区别在于，采用的环氧化合物为b6，收率为87％。
实施例65
与实施例1的区别在于，采用的环氧化合物为b7，收率为89％。
实施例66
与实施例1的区别在于，采用的环氧化合物为b8，收率为47％。
根据上述各实施例的结果可以看出，采用本申请的方法适用底物范围较广、反应条件温和。某些实施例的收率稍低，可能的原因是反应条件还需要调整或者是采用的溶剂等需要进行调整。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请所提供的方法，不仅操作简便易行，而且后处理只需简单的常规分离步骤即可得到纯产物，同时由于环氧化合物成本低廉，因此可以大大降低了生产操作成本和三废处理的风险和成本。且上述方法在使用时，反应条件温和，能够兼容各种不同取代基和官能团，对各种不同结构类型的酰胺均能取得很好的收率，底物适用范围广。即本发明为酰胺醇解提供了一条环境友好，经济实用的高效方法。本申请的上述醇解反应不会受到上一步C-H活化反应体系中的杂质影响，节省中间体纯化步骤，可以C-H活化和酰胺醇解两步反应连投。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (11)

  1. 一种酰胺醇解的方法，其特征在于，所述方法包括使用环氧化合物作为促进剂，在碱性条件下对含酰胺化合物进行醇解。
  2. 根据权利要求1所述的方法，其特征在于，以环氧化合物和酰胺化合物的摩尔比计，所述环氧化合物和所述含酰胺化合物的用量比为1～5：1。
  3. 根据权利要求1所述的方法，其特征在于，所述含酰胺化合物具有通式I，所述通式I为
    Figure PCTCN2017083498-appb-100001
    R1，R2各自独立地选自烷基、芳基、取代烷基和取代芳基中的任意一种，优选所述烷基选自C1～C18的烷基中的任意一种，优选所述取代烷基的主链碳原子数为C1～C18中的任意一种，优选所述取代烷基为单取代烷基或多取代烷基，优选所述取代烷基中的取代基选自芳基、芳香杂环取代基、环烷烃、杂环烷烃、烯基和炔基中的任意一种或多种的组合取代基。
  4. 根据权利要求1所述的方法，其特征在于，所述环氧化合物具有通式II，所述通式II为
    Figure PCTCN2017083498-appb-100002
    所述R3和所述R4各自独立地选自H、烷基和芳基中的任一种，优选所述烷基选自C1～C18的烷基中的任意一种。
  5. 根据权利要求1至4中任一项所述的方法，其特征在于，所述方法包括：
    将所述含酰胺化合物、所述环氧化合物、pH值调节剂和溶剂混合，形成碱性反应体系，优选所述碱性反应体系的pH值为7.5～9.5；
    使所述碱性反应体系在50～150℃下反应以对所述含酰胺化合物进行醇解。
  6. 根据权利要求5所述的方法，其特征在于，所述pH值调节剂为弱酸或弱碱，优选所述pH值调节剂选自CF3CO2K、CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、LiHCO3、CsF、KF、NaF、LiF、Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、Na3PO4、苯甲酸钠、四甲基乙二胺、N-N二异丙基乙胺和三乙胺中的任意一种或多种。
  7. 根据权利要求5所述的方法，其特征在于，所述溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、异戊醇、乙二醇、丙三醇、1,2-二甲氧基乙烷、乙二醇二乙醚、2-甲氧基乙基醚、2-乙氧基乙基醚和吡咯中的任意一种或多种。
  8. 根据权利要求5所述的方法，其特征在于，所述含酰胺化合物为
    Figure PCTCN2017083498-appb-100003
    所述环氧化合物为甲基缩水甘油醚，所述pH值调节剂为KOAc，所述溶剂为乙醇。
  9. 根据权利要求8所述的方法，其特征在于，所述碱性反应体系在80～100℃下反应以对所述含酰胺化合物进行醇解。
  10. 根据权利要求8所述的方法，其特征在于，在所述醇解完成后，所述方法还包括：
    对所述醇解产物进行减压去溶剂，得到残留物；
    将所述残留物与水混合形成混合物；
    调节所述混合物的pH值至3.5～4.5后采用正己烷进行萃取，得到有机相；以及
    对所述有机相进行干燥、过滤。
  11. 根据权利要求8所述的方法，其特征在于，在所述醇解完成后，所述方法还包括：
    对所述醇解产物进行减压去溶剂，得到残留物；
    采用硅胶柱层析对所述残留物进行纯化。
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