CN104140387A - Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds - Google Patents
Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds Download PDFInfo
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- CN104140387A CN104140387A CN201310642349.0A CN201310642349A CN104140387A CN 104140387 A CN104140387 A CN 104140387A CN 201310642349 A CN201310642349 A CN 201310642349A CN 104140387 A CN104140387 A CN 104140387A
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- 0 CC(C)(C)OC(N(C1)CC1OC1=CC(C)=C(*)CC=C1)=O Chemical compound CC(C)(C)OC(N(C1)CC1OC1=CC(C)=C(*)CC=C1)=O 0.000 description 1
- ZGBUABNKJMXMTN-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC1Oc(cc1)ccc1C(OC)=O)=O Chemical compound CC(C)(C)OC(N(C1)CC1Oc(cc1)ccc1C(OC)=O)=O ZGBUABNKJMXMTN-UHFFFAOYSA-N 0.000 description 1
- CTNHCTDBYOYTEG-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC1Oc1ccccc1)=O Chemical compound CC(C)(C)OC(N(C1)CC1Oc1ccccc1)=O CTNHCTDBYOYTEG-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a preparation method for N-tert-butyloxycarbonyl-azetidine aromatic ether/aromatic heterocyclic ether compounds, and belongs to the technical field of organic synthesis. The method is as follows: by taking 1-tert-butyloxycarboryl-3-iodoazetidine and arylboronic acid or nitrogen-containing heterocyclic boric acid as materials, producing the N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compound by virtue of copper-catalyzed carbon-oxygen cross-coupling reaction. The reaction conditions are gentle, the substrate applicability is good, the reaction specificity is strong, and a medium to high yield can be obtained. A catalyst system for the reaction has good stability, efficient catalytic activity and extensive applicability, and can effectively avoid damages of strong-basicity reaction conditions on a certain functional groups; moreover, the materials are cheap and easy to obtain, so that the cost is low.
Description
Technical field
The present invention is specifically related to a kind of preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds, belongs to technical field of organic synthesis.
Background technology
N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds is the important pharmaceutical intermediate of a class, especially in treatment obesity and metabolic syndrome, plays very important effect.Mainly contain at present three kinds of methods and synthesize azetidine aromatic oxide/fragrant heterocyclic ether compounds.
(1) nucleophilic substitution reaction of 3-hydroxy azetidine compounds and aryl halogen (reaction equation as shown in Equation 1), referring to patent WO2008076562A1, WO2008089580A1, WO2009050522A1, WO2010043052A1 and WO2010059393A1.
(2) nucleophilic substitution reaction of 3-iodine azetidin compounds and phenolic compound (reaction equation as shown in Equation 2), referring to patent WO2009050522A1 and WO2012084711.
(3) light that 3-hydroxy azetidine compounds and phenolic compound occur prolongs reaction (Mitsunobu reaction) (reaction equation as shown in Equation 3), referring to (Bioorg.Med.Chem.Lett, 2011) such as patent WO2007143823A1 and E.Isabel.
But above-mentioned three kinds of methods still have limitation in some respects.For example, nucleophilic substitution reaction needs highly basic conventionally, and only has with the aryl halogen of electron withdrawing group and easily participate in reaction, and light prolongs reaction and can produce triphenylphosphine oxide, and to environment, the condition of preparing some phenolic compound requirement is harsher.Therefore, explore a kind of novel, method is carried out synthetic aroma azetidine ether compound and is necessary efficiently.
Summary of the invention
The object of this invention is to provide a kind of preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds.
In order to realize above object, the technical solution adopted in the present invention is:
A kind of preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds, taking 1-tert-Butoxycarbonyl-3-iodoazetidine and aryl boric acid or nitrogen heterocyclic ring boric acid as raw material, copper catalyzed carbon oxygen cross-coupling reaction generates N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds.
Described copper catalyzed carbon oxygen cross-coupling reaction is under copper catalyst exists, first there is the oxidation hydrogenation of aryl boric acid or nitrogen heterocyclic boric acid, generate phenolic compound, phenolic compound again with 1-tert-Butoxycarbonyl-3-iodoazetidine generation carbon oxygen cross-coupling reaction (being C-O cross-coupling reaction), finally generate N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds.
Reaction equation is as shown in Equation 4:
In formula: Ar is aromatic ring or fragrant heterocycle.
Described 1-tert-Butoxycarbonyl-3-iodoazetidine is 1:(1.2～2.5 with the ratio of the amount of substance of aryl boric acid or nitrogen heterocyclic ring boric acid).
Described nitrogen heterocyclic ring boric acid comprises again pyridines boric acid, pyroles boric acid, indoles boric acid, imidazoles boric acid, quinoline boric acid and miazines boric acid.
Described aryl boric acid comprises phenylo boric acid and substituted benzene boric acid.Substituted benzene boric acid comprises that again (in alkyl, the number of carbon is less than 10 to alkyl substituted benzene boric acid, as 4-methylphenylboronic acid, 2-methylphenylboronic acid etc.), halogeno-benzene boric acid is (as 4-fluorobenzoic boric acid, 3-fluorobenzoic boric acid, 2-fluorobenzoic boric acid, 4-chlorobenzene boric acid, 3-bromobenzene boric acid etc.), itrile group substituted benzene boric acid is (as 4-itrile group phenylo boric acid, 3-itrile group phenylo boric acid etc.), nitro substituted benzene boric acid (as 3-oil of mirbane boric acid etc.), (in alcoxyl carboxyl, the number of carbon is less than 10 to alcoxyl carboxyl substituted phenylo boric acid, as 4-methoxy carboxyl phenylo boric acid etc.), ketone group substituted benzene boric acid (as 4-ethyl ketone base phenylo boric acid etc.) etc.
Described pyridines boric acid comprises pyridine boric acid (as 4-pyridine boric acid, 3-pyridine boric acid etc.) and substituted pyridines boric acid.Described substituted pyridines boric acid comprises that again (in alkyl, the number of carbon is less than 10 to alkyl substituted pyridines boric acid, as 3-methyl-4-pyridine boric acid etc.), haloperidid boric acid (2-pyridine boric acid as fluoro-in 3-etc.), (in alkoxyl group, the number of carbon is less than 10 to alkoxyl group substituted pyridines boric acid, as 4-oxyethyl group-3-pyridine boric acid etc.), haloalkyl substituted pyridines boric acid (in haloalkyl, the number of carbon is less than 10, as 4-trifluoromethyl-3-pyridine boric acid, 5-trifluoromethyl-3-pyridine boric acid etc.) etc.
Under the condition that described copper catalyzed carbon oxygen cross-coupling reaction exists at alkali, copper catalyst, part and solvent, carry out, temperature of reaction is 70～90 DEG C, and the reaction times is 20～24 hours.
Described copper catalyst is any in cuprous iodide, cuprous chloride, cupric chloride, cupric oxide, copper powder.
Described part is Tetramethyl Ethylene Diamine (TMEDA), N
1, N
1, N
2-trimethylammonium quadrol, N
1, N
1-dimethyl-ethylenediamine, quadrol, L-PROLINE, D-PROLINE, L-PROLINE/D-PROLINE (1:1), (1R, 2R)-2-Trans-4-Amino Cyclohexanol, (1S, 2S)-2-Trans-4-Amino Cyclohexanol, 1, any in 2-cyclohexanediamine.Wherein, copper catalyst is 1:(0.5～2 with the ratio of the amount of substance of part).Copper catalyst is 1:(7～20 with the ratio of the amount of substance of 1-tert-Butoxycarbonyl-3-iodoazetidine).
Described alkali is any in Tripotassium phosphate, salt of wormwood, sodium hydroxide, cesium carbonate, cesium fluoride, Potassium monofluoride.Wherein, alkali is 1:(0.5～1 with the ratio of the amount of substance of 1-tert-Butoxycarbonyl-3-iodoazetidine).
Described solvent is any in DMF (DMF), N,N-dimethylacetamide (DMA), N,N-dimethylacetamide/water (10:1, V/V), methyl-sulphoxide (DMSO), N-Methyl pyrrolidone (NMP).Wherein, the solvent load of every mole of 1-tert-Butoxycarbonyl-3-iodoazetidine is 4～6 liters.
Preferably, a kind of preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds, taking 1-tert-Butoxycarbonyl-3-iodoazetidine and phenylo boric acid as raw material, copper catalyzed carbon oxygen cross-coupling reaction generates N-tertbutyloxycarbonyl-azetidine phenyl ether; Wherein, the ratio of the amount of substance of 1-tert-Butoxycarbonyl-3-iodoazetidine and phenylo boric acid (aryl boric acid), Tripotassium phosphate (alkali), the sub-ketone of iodate (copper catalyst), L-PROLINE (part) is 1:1.5:2:0.1:0.1, every mole of 1-tert-Butoxycarbonyl-3-iodoazetidine adds 4 liters of N,N-dimethylacetamide (solvent).More have choosing, the temperature of above-mentioned copper catalyzed carbon oxygen cross-coupling reaction is 80 DEG C, and the reaction times is 22 hours.
A preparation method for N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds, further comprising the steps of: to react complete, be cooled to room temperature, reaction solution dilutes by ethyl acetate, and organic phase successively water, saturated aqueous common salt is cleaned, and filters, the concentrated crude product that to obtain, repurity and get final product.
Beneficial effect of the present invention:
It is raw material that the present invention adopts economy, stable aryl boric acid or nitrogen heterocyclic ring boric acid, under copper catalyst exists, first there is the oxidation hydrogenation of aryl boric acid or nitrogen heterocyclic boric acid, generate phenolic compound, phenolic compound again with 1-tert-Butoxycarbonyl-3-iodoazetidine generation carbon oxygen cross-coupling reaction, finally generate N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds.This reaction conditions gentleness, good substrate applicability, reaction specificity is strong.Its catalyst system has satisfactory stability, efficiently catalytic activity and suitability widely, can effectively avoid the destruction of strong basicity reaction conditions to some functional group, and material is cheap and easy to get, and cost is low.
Embodiment
Following embodiment is only described in further detail the present invention, but does not form any limitation of the invention.
Embodiment 1
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), DMF 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 37mg target product, yield 30%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 4.01 (dd, J
1=4.1Hz, J
2=9.9Hz, 2H), 4.29 (dd, J
1=6.5Hz, J
2=9.9Hz, 2H), 4.85-4.90 (m, 1H), 6.74 (d, J=7.8Hz, 2H), 6.99 (t, J=7.4Hz, 1H), 7.27-7.31 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.6,65.7,79.9,114.7,121.7,129.9,156.3,156.7; ESI-MS m/z=272 (M+23).
Embodiment 2
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), salt of wormwood (138.2mg, 2mmol), DMF 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 22mg target product, yield 18%.
Embodiment 3
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.55mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), sodium hydroxide (40.0mg, 2mmol), DMF 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 21mg target product, yield 17%.
Embodiment 4
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), cesium carbonate (325.8mg, 2mmol), DMF 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 27mg target product, yield 22%.
Embodiment 5
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Potassium monofluoride (58.1mg, 2mmol), DMF 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 16mg target product, yield 13%.
Embodiment 6
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 42mg target product, yield 34%.
Embodiment 7
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), DMF/water (v=10:1) 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 36mg target product, yield 29%.
Embodiment 8
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), methyl-sulphoxide 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 25mg target product, yield 20%.
Embodiment 9
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N-Methyl pyrrolidone 2mL.Under oil bath condition, reaction solution is heated to 120 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 34mg target product, yield 27%.
Embodiment 10
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), TMEDA (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 43mg target product, yield 34%.
Embodiment 11
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), N
1, N
1, N
2-trimethylammonium quadrol (5.1mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 54mg target product, yield 43%.
Embodiment 12
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), N
1, N
1-dimethyl-ethylenediamine (4.4mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 57mg target product, yield 46%.
Embodiment 13
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), quadrol (3.0mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 64mg target product, yield 51%.
Embodiment 14
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 15
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), D-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 16
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE/D-PROLINE (m=1:1) (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 17
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), (1R, 2R)-2-Trans-4-Amino Cyclohexanol (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 56mg target product, yield 45%.
Embodiment 18
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), (1S, 2S)-2-Trans-4-Amino Cyclohexanol (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 56mg target product, yield 45%.
Embodiment 19
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), 1,2-cyclohexanediamine (5.7mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 59mg target product, yield 47%.
Embodiment 20
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous chloride (5.0mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 21
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cupric chloride (6.7mg, 10mol%), L-PROLINE (5.78mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 55mg target product, yield 44%.
Embodiment 22
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), copper powder (3.2mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 40mg target product, yield 32%.
Embodiment 23
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 70 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 56mg target product, yield 45%.
Embodiment 24
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (121.9mg, 1.0mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 90 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 56mg target product, yield 45%.
Embodiment 25
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (91.5mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 26
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (73.2mg, 0.6mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 24 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 56mg target product, yield 45%.
Embodiment 27
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (91.5mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 65mg target product, yield 52%.
Embodiment 28
The preparation of N-tertbutyloxycarbonyl-azetidine phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), phenylo boric acid (91.5mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 20 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 57mg target product, yield 46%.
Embodiment 29
The preparation of N-tertbutyloxycarbonyl-azetidine-4-fluorophenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-fluorobenzoic boric acid (104.9mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 76mg target product, yield 57%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 3.98 (dd, J
1=4.2Hz, J
2=10.4Hz, 2H), 4.25-4.29 (m, 2H), 4.79-4.84 (m, 1H), 6.65-6.71 (m, 2H), 6.95-7.00 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.4,56.4,66.1,79.9,115.6 (d, J=8.0Hz), 116.2 (d, J=23.3Hz), 152.7,156.5,157.5 (d, J=275.4Hz); ESI-MS m/z=290 (M+23).
Embodiment 30
The preparation of N-tertbutyloxycarbonyl-azetidine-3-fluorophenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 3-fluorobenzoic boric acid (104.9mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:100-1:80 as developping agent, and column chromatography separates, and obtains 76mg target product, yield 58%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, DMSO-d6): δ 1.38 (s, 9H); 3.77 (d, J=6.5Hz, 2H); 4.30 (s, 2H), 4.97-5.02 (m; 1H), 6.68-6.73 (m, 2H); 6.79-6.83 (m; 1H), 7.30-7.36 (m, 1H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.4,66.1; 80.1,102.7 (d, J=24.9Hz); 108.6 (d, J=21.2Hz), 110.3 (d; J=2.9Hz), 130.7 (d, J=9.9Hz); 156.2,158.0 (d, J=10.8Hz); 163.8 (d, J=244.5Hz); ESI-MSm/z=290 (M+23).
Embodiment 31
The preparation of N-tertbutyloxycarbonyl-azetidine-4-chloro-phenyl-ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-chlorobenzene boric acid (117.3mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:8 as developping agent, and thin-layer chromatography separates, and obtains 72mg target product, yield 51%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.44 (s, 9H), 3.96-4.00 (m, 2H), 4.26-4.30 (m, 2H), 4.80-4.86 (m, 1H), 6.64-6.68 (m, 2H), 7.21-7.25 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.4,66.0,80.1,116.0,126.7,129.8,155.3,156.2; ESI-MS m/z=306 (M+23).
Embodiment 32
The preparation of N-tertbutyloxycarbonyl-azetidine-3-bromophenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 3-bromobenzene boric acid (150.6mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:50-1:30 as developping agent, and column chromatography separates, and obtains 84mg target product, yield 51%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 3.99 (dd, J
1=4.0Hz, J
2=9.8Hz, 2H), 4.29 (dd, J
1=6.4Hz, J
2=9.8Hz, 2H), 4.82-4.87 (m, 1H), 6.66-6.69 (m, 1H), 6.89 (m, 1H), 7.11-7.17 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.4,56.3,66.0,80.0,113.5,118.0,123.1,124.8,130.9,156.1,157.4; ESI-MS m/z=350 (M+23).
Embodiment 33
The preparation of N-tertbutyloxycarbonyl-azetidine-4-itrile group phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-itrile group phenylo boric acid (110.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.76mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:40-1:10 as developping agent, and column chromatography separates, and obtains 99mg target product, yield 72%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.44 (s, 9H), 3.99-4.02 (m, 2H), 4.30-4.34 (m, 2H), 4.89-4.94 (m, 1H), 6.78-6.81 (m, 2H), 7.58-7.61 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.3,66.3,80.3,105.3,115.5,119.0,134.4,156.1,160.0; ESI-MS m/z=297 (M+23).
Embodiment 34
The preparation of N-tertbutyloxycarbonyl-azetidine-3-itrile group phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 3-itrile group phenylo boric acid (110.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.76mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:40-1:2 as developping agent, and column chromatography separates, and obtains 70mg target product, yield 51%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 4.00 (dd, J
1=4.0Hz, J
2=10.5Hz, 2H), 4.30-4.35 (m, 2H), 4.85-4.91 (m, 1H), 6.97-7.01 (m, 2H), 7.28-7.30 (m, 1H), 7.39 (like t, 1H);
13c NMR (100MHz, CDCl
3): δ 28.4,56.2,66.2,80.1,113.6,117.7,118.4,119.8,125.5,130.8,156.1,156.8; ESI-MS m/z=297 (M+23).
Embodiment 35
The preparation of N-tertbutyloxycarbonyl-azetidine-3-nitrophenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 3-oil of mirbane boric acid (110.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.76mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:40-1:10 as developping agent, and column chromatography separates, and obtains 87mg target product, yield 59%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 4.02 (dd, J
1=4.0Hz, J
2=10.0Hz, 2H), 4.36 (dd, J
1=6.5Hz, J
2=10.0Hz, 2H), 4.93-4.98 (m, 1H), 7.12 (dd, J
1=2.3Hz, J
2=8.2Hz, 1H), 7.46 (t, J=8.2Hz, 1H), 7.54 (t, J=2.2Hz, 1H), 7.87 (dd, J
1=1.5Hz, J
2=8.2Hz, 1H);
13cNMR (100MHz, CDCl
3): δ 28.3,56.1,66.4,80.1,109.0,116.7,121.6,130.4,149.3,156.0,157.1; ESI-MS m/z=317 (M+23).
Embodiment 36
The preparation of N-tertbutyloxycarbonyl-azetidine-4-methoxy carboxyl phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-methoxy carboxyl phenylo boric acid (135.0mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:4 as developping agent, and thin-layer chromatography separates, and obtains 108mg target product, yield 70%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 3.89 (s, 3H), 4.01 (dd, J
1=4.1Hz, J
2=10.4Hz, 2H), 4.30-4.34 (m, 2H), 4.90-4.95 (m, 1H), 6.74-6.77 (m, 2H), 7.97-8.01 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 28.5,52.1,56.4,66.1,80.2,114.4,123.7,132.0,156.2,160.4,166.8; ESI-MS m/z=330 (M+23).
Embodiment 37
The preparation of N-tertbutyloxycarbonyl-azetidine-4-ethyl ketone base phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-ethyl ketone base phenylo boric acid (100.0mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:30-1:10 as developping agent, and column chromatography separates, and obtains 79mg target product, yield 67%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 2.56 (s, 3H), 4.01 (dd, J
1=4.0Hz, J2=10.2Hz, 2H), 4.33 (dd, J
1=6.4Hz, J
2=10.3Hz, 2H), 4.91-4.97 (m, 1H), 6.76-6.79 (m, 2H), 7.91-7.95 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 26.3,28.3,56.2,65.9,80.0,114.3,130.7,131.1,156.0,160.4,196.6; ESI-MS m/z=314 (M+23); HRMS (ESI
+) calcd for C
16h
21nO
4(M+Na
+) 314.1363; Found:314.1364.
Embodiment 38
The preparation of N-tertbutyloxycarbonyl-azetidine-4-methyl phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-methylphenylboronic acid (102.0mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:80-1:50 as developping agent, and column chromatography separates, and obtains 38mg target product, yield 29%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.44 (s, 9H), 2.28 (s, 3H), 3.99 (dd, J
1=4.2Hz, J
2=10.2Hz, 2H), 4.25-4.29 (m, 2H), 4.81-4.87 (m, 1H), 6.62-6.65 (m, 2H), 7.08 (d, J=8.2Hz, 2H);
13c NMR (100MHz, CDCl
3): δ 20.6,28.5,56.6,65.8,79.9,114.6,130.3,131.0,154.6,156.3; ESI-MS m/z=286 (M+23).
Embodiment 39
The preparation of N-tertbutyloxycarbonyl-azetidine-2-methyl phenyl ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 2-methylphenylboronic acid (102.0mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:80-1:50 as developping agent, and column chromatography separates, and obtains 62mg target product, yield 47%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 2.24 (s, 3H), 4.01 (dd, J
1=4.2Hz, J
2=10.1Hz, 2H), 4.31 (dd, J
1=6.5Hz, J
2=10.2Hz, 2H), 4.85-4.90 (m, 1H), 6.44 (d, J=8.0Hz, 1H), 6.89 (like t, 1H), 7.11 (t, J=7.8Hz, 1H), 7.16 (d, J=7.4Hz, 1H);
13c NMR (100MHz, CDCl
3): δ 16.2,28.4,65.6,79.8,110.7,121.2,126.8,127.0,131.1,154.8,156.2; ESI-MS m/z=286 (M+23).
Embodiment 40
The preparation of N-tertbutyloxycarbonyl-azetidine-4-pyridine ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 4-pyridine boric acid (92.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=2:1 as developping agent, and thin-layer chromatography separates, and obtains 59mg target product, yield 47%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 4.02 (dd, J
1=3.8Hz, J
2=10.0Hz, 2H), 4.34 (dd, J
1=6.4Hz, J
2=9.9Hz, 2H), 4.93-4.98 (m, 1H), 6.74 (d, J=6.0Hz, 2H), 8.48 (d, J=5.2Hz, 2H);
13c NMR (100MHz, CDCl
3): δ 28.5,66.3,80.3,110.8,150.4,156.1,163.6; ESI-MS m/z=251 (M+1).
Embodiment 41
N-tertbutyloxycarbonyl-azetidine-4-(2-picoline) preparation of ether, comprise the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 2-picoline-4-boric acid (102.7mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate as developping agent, and thin-layer chromatography separates, and obtains 67mg target product, yield 50%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.44 (s, 9H), 2.58 (s, 3H), 4.00 (dd, J
1=3.9Hz, J
2=10.2Hz, 2H), 4.31-4.35 (m, 2H), 4.91-4.96 (m, 1H), 6.55-6.57 (m, 2H), 8.35 (d, J=6.0Hz, 1H);
13c NMR (100MHz, CDCl
3): δ 24.0,28.3,66.1,80.2,108.0,109.9,149.5,156.0,159.8,163.8; ESI-MS m/z=265 (M+1).
Embodiment 42
The preparation of N-tertbutyloxycarbonyl-azetidine-3-pyridine ether, comprises the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 3-pyridine boric acid (92.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=2:1 as developping agent, and thin-layer chromatography separates, and obtains 57mg target product, yield 46%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.45 (s, 9H), 4.02 (dd, J
1=3.7Hz, J
2=10.0Hz, 2H), 4.34 (dd, J
1=6.2Hz, J
2=9.9Hz, 2H), 4.91-4.97 (m, 1H), 7.17 (dd, J
1=1.8Hz, J
2=8.4Hz, 1H), 7.33 (dd, J
1=4.7Hz, J
2=8.4Hz, 1H), 8.19 (d, J=2.2Hz, 1H), 8.30 (d, J=4.4Hz, 1H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.3,66.5,80.2,122.8,124.6,136.6,142.2,153.3,156.2; ESI-MS m/z=251 (M+1).
Embodiment 43
N-tertbutyloxycarbonyl-azetidine-3-(6-ethoxy pyridine) preparation of ether, comprise the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 2-ethoxy pyridine-5-boric acid (125.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:30-1:2 as developping agent, and column chromatography separates, and obtains 29mg target product, yield 20%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, DMSO-d6): δ 1.28 (t, J=7.0Hz, 3H), 1.38 (s, 9H), 3.78 (d, J=6.9Hz, 2H), 4.21 (q, J=7.0Hz, 2H), 4.23-4.28 (m, 2H), 4.92-4.97 (m, 1H), 6.74 (d, J=9.0Hz, 1H), 7.30 (dd, J
1=3.1Hz, J
2=9.0Hz, 1H), 7.70 (d, J=3.0Hz, 1H);
13c NMR (100MHz, DMSO-d6): δ 14.6,28.1,61.3,66.5,79.1,111.3,127.7,132.1,147.9,155.7,158.3; ESI-MS m/z=295 (M+1).
Embodiment 44
N-tertbutyloxycarbonyl-azetidine-3-(6-5-flumethiazine) preparation of ether, comprise the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 2-5-flumethiazine-5-boric acid (143.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:3 as developping agent, and column chromatography separates, and obtains 75mg target product, yield 47%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, DMSO-d6): δ 1.38 (s, 9H), 3.85 (d, J=7.3Hz, 2H), 4.32-4.36 (m, 2H), 5.14-5.19 (m, 1H), 7.47 (dd, J
1=2.8Hz, J
2=8.7Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 8.39 (d, J=2.8Hz, 1H);
13c NMR (100MHz, DMSO-d6): δ 28.1,55.9,66.8,79.2,121.9 (q, J=272.0Hz), 122.1 (q, J=2.7Hz), 122.2,138.8,139.3 (q, J=34.0Hz), 155.0,155.6; ESI-MSm/z=319 (M+1).
Embodiment 45
N-tertbutyloxycarbonyl-azetidine-3-(5-5-flumethiazine) preparation of ether, comprise the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 5-5-flumethiazine-3-boric acid (143.2mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:30-1:2 as developping agent, and column chromatography separates, and obtains 54mg target product, yield 34%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, DMSO-d6): δ 1.38 (s, 9H); 3.84 (d, J=6.9Hz, 2H); 4.34 (m, 2H), 5.17-5.23 (m; 1H), 7.64 (s, 1H); 8.53 (d, J=2.6Hz, 1H); 8.60 (s, 1H);
13cNMR (100MHz, DMSO-d6): δ 27.9,55.4,66.7,79.1,118.3 (q, J=3.5Hz), 123.3 (q, J=271.2Hz), 125.9 (q, J=31.9Hz), 138.7 (q, J=4.5Hz), 142.0,152.5,155.5ESI-MS m/z=319 (M+1).
Embodiment 46
N-tertbutyloxycarbonyl-azetidine-2-(6-fluorine pyridine) preparation of ether, comprise the following steps:
In dry Schlenk pipe, add magneton, 1-tert-Butoxycarbonyl-3-iodoazetidine (141.6mg, 0.5mmol), 2-fluorine pyridine-6-boric acid (140.9mg, 0.75mmol), cuprous iodide (9.5mg, 10mol%), L-PROLINE (5.8mg, 10mol%), Tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylacetamide 2mL.Under oil bath condition, reaction solution is heated to 80 DEG C, and the reaction times is 22 hours.Stopped reaction, is cooled to room temperature, and reaction solution dilutes by ethyl acetate, and organic phase washes twice with water, and saturated common salt is washed once, uses MgSO
4dry, filter, concentrated, vacuumize.Thick product is taking ethyl acetate/petroleum ether=1:80 as developping agent, and column chromatography separates, and obtains 42mg target product, yield 31%.The nuclear-magnetism of this compound characterizes as follows
1h NMR (400MHz, CDCl
3): δ 1.44 (s, 9H), 3.95-3.98 (m, 2H), 4.30-4.35 (m, 2H), 5.24-5.29 (m, 1H), 6.50 (dd, J
1=2.2Hz, J
2=7.7Hz, 1H), 6.64 (dd, J
1=1.2Hz, J
2=8.0Hz, 1H), 7.68 (q, J=8.0Hz, 1H);
13c NMR (100MHz, CDCl
3): δ 28.5,56.6,65.2,79.9,101.0 (d; J=34.6Hz), 107.5 (d, J=5.0Hz), 143.1 (d, J=8.3Hz); 156.4,161.3 (d, J=68.0Hz), 162.5 (d, J=194.3Hz); ESI-MS m/z=291 (M+23).
Claims (10)
1. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds, it is characterized in that: taking 1-tert-Butoxycarbonyl-3-iodoazetidine and aryl boric acid or nitrogen heterocyclic ring boric acid as raw material, copper catalyzed carbon oxygen cross-coupling reaction generates N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds.
2. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 1, is characterized in that: described 1-tert-Butoxycarbonyl-3-iodoazetidine is 1:(1.2～2.5 with the ratio of the amount of substance of aryl boric acid or nitrogen heterocyclic ring boric acid).
3. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 1, is characterized in that: described aryl boric acid is any in phenylo boric acid, alkyl substituted benzene boric acid, halogeno-benzene boric acid, itrile group substituted benzene boric acid, nitro substituted benzene boric acid, alcoxyl carboxyl substituted phenylo boric acid, ketone group substituted benzene boric acid.
4. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 1, it is characterized in that: described nitrogen heterocyclic ring boric acid is pyridines boric acid, comprise any in pyridine boric acid, alkyl substituted pyridines boric acid, haloperidid boric acid, alkoxyl group substituted pyridines boric acid, haloalkyl substituted pyridines boric acid.
5. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 1, it is characterized in that: under the condition that described copper catalyzed carbon oxygen cross-coupling reaction exists at alkali, copper catalyst, part and solvent, carry out, temperature of reaction is 70～90 DEG C, and the reaction times is 20～24 hours.
6. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 5, is characterized in that: described copper catalyst is any in cuprous iodide, cuprous chloride, cupric chloride, cupric oxide, copper powder.
7. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 5, is characterized in that: described part is Tetramethyl Ethylene Diamine, N
1, N
1, N
2-trimethylammonium quadrol, N
1, N
1-dimethyl-ethylenediamine, quadrol, L-PROLINE, D-PROLINE, L-PROLINE/D-PROLINE (1:1), (1R, 2R)-2-Trans-4-Amino Cyclohexanol, (1S, 2S)-2-Trans-4-Amino Cyclohexanol, 1, any in 2-cyclohexanediamine.
8. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 5, it is characterized in that: described solvent is N, dinethylformamide, N, any in N-N,N-DIMETHYLACETAMIDE, N,N-dimethylacetamide/water, methyl-sulphoxide, N-Methyl pyrrolidone.
9. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 5, it is characterized in that: taking 1-tert-Butoxycarbonyl-3-iodoazetidine and phenylo boric acid as raw material, copper catalyzed carbon oxygen cross-coupling reaction generates N-tertbutyloxycarbonyl-azetidine phenyl ether; Wherein, 1-tert-Butoxycarbonyl-3-iodoazetidine is 1:1.5:2:0.1:0.1 with the ratio of the amount of substance of phenylo boric acid, Tripotassium phosphate, the sub-ketone of catalyzer iodate, L-PROLINE, every mole of 1-tert-Butoxycarbonyl-3-iodoazetidine adds 4～6 liters of N,N-dimethylacetamide.
10. the preparation method of N-tertbutyloxycarbonyl-azetidine aromatic oxide/fragrant heterocyclic ether compounds according to claim 5, it is characterized in that: further comprising the steps of: react complete, be cooled to room temperature, reaction solution dilutes by ethyl acetate, organic phase successively water, saturated aqueous common salt is cleaned, filter the concentrated crude product that to obtain, repurity and get final product.
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