CN103012232B - Method for preparing 3-halogenation-2,5-pyrroline compound - Google Patents
Method for preparing 3-halogenation-2,5-pyrroline compound Download PDFInfo
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Abstract
The invention discloses a method for preparing a 3-halogenation-2,5-pyrroline compound. The method comprises the following steps of: reacting a 3-pyrrolidone compound shown in the general formula (I) as a raw material with hydrazine hydrate and hydrazine anhydrous to generate a compound shown in the general formula (II); then reacting with copper halide to prepare a dihalogenation product shown in the general formula (III); and removing single-molecule hydrogen halide under the action of alkali to obtain a target product, namely a 3-halogenation-2,5-pyrroline compound shown in the general formula (IV). The method disclosed by the invention overcomes the defects of a document and has the advantages of easiness for raw material obtaining, moderate reaction condition, simpleness and easiness for operation, good reaction selectivity, high yield and environmental friendliness.
Description
Technical field
The present invention relates to chemical synthesis technical field, be specifically related to a kind of 3-halo-2, the preparation method of 5-pyrroline compound.
Background technology
3-halo-2, the method for 5-pyrroline compound is compound that a class is more novel and important medicine intermediate, has a wide range of applications.Have no at present bibliographical information about the synthetic method of this compounds.
Summary of the invention
The present invention has made up this shortcoming, provide in a creative way a kind of for logical formula IV 3-halo-2, the preparation of 5-pyrroline compound, by take, to lead to formula I 3-pyrrolidones be raw material for it, through reacting with hydrazine hydrate and anhydrous hydrazine, generate formula II compound, react with copper halide again and make formula III dihalo product, under the effect of alkali, eliminate an one's share of expenses for a joint undertaking hydrogen halide selectivity and obtain target product formula IV 3-halo-2, the method for 5-pyrroline compound compared with highland.
A kind of logical formula IV 3-halo-2, the preparation method of 5-pyrroline compound, it is characterized in that to lead to formula I 3-pyrrolidones be raw material by take, through reacting with hydrazine hydrate and anhydrous hydrazine, generate formula II compound, react with copper halide again and make formula III dihalo product, under the effect of alkali, eliminate a part hydrogen halide and obtain target product formula IV 3-halo-2, the method for 5-pyrroline compound
。
R represent methylidene, benzyl or tertbutyloxycarbonyl in described general formula; X represents chlorine atom or bromine atoms.
The mol ratio of described logical formula I compounds and hydrazine hydrate and anhydrous hydrazine is 1:1:0.5.
The mol ratio of described formula II compounds and copper halide and triethylamine is 1:6:3.
The mol ratio of described formula III class dihalo thing and DBU is 1:1.1.
Described formula III class dihalo thing and the DBU of utilizing eliminates one's share of expenses for a joint undertaking hydrogen halide generation formula IV compound and formula (V) compound for 2～5 hours in reflux in toluene, and the ratio of formula IV compound and formula (V) compound is about 90:10.
The present invention provides a kind of 3-of preparation halo-2 in a creative way, and the method for 5-pyrroline compound has made up the shortcoming of prior art, and the method therefor raw material reaction conditions gentleness that is easy to get, simple, and good reaction selectivity, yield are high, environmental friendliness.
Embodiment
The technical scheme that the present invention adopted is for achieving the above object: the first step first utilizes 3-pyrrolidones and hydrazine hydrate in ethanol, to stir 1～2 hour, concentrate out the mixture that obtains 3-pyrrolidone hydrazone compounds and two 3-pyrrolidone hydrazone compounds after solvent, warp and anhydrous hydrazine effect, make two 3-pyrrolidone hydrazone compounds be converted into 3-pyrrolidone hydrazone compounds, prepare 3-pyrrolidone hydrazone compounds, this step yield calculates by 100%.Second step utilizes 3-pyrrolidone hydrazone compounds at 0 ℃～-10 ℃, to react 4～8 hours in anhydrous methanol with copper halide and triethylamine, through ammoniacal liquor cancellation, toluene extraction, organic layer is respectively washed once through ammoniacal liquor and the saturated NaCl aqueous solution, underpressure distillation obtains 3 by 2 of two corresponding halogen atoms replacements, 5-pyrroline compound, yield 70～78%.3 of obtaining of the 3rd step utilization by two halogen atoms, replaced 2,5-pyrroline compound and DBU eliminate an one's share of expenses for a joint undertaking hydrogen halide for 4～6 hours in reflux in toluene and generate formula IV compound and formula (V) compound, be down to after room temperature, with 0.4mol/L HCl, be washed till pH value 3～4, organic layer is through saturated NaHCO
3solution and saturated NaCl solution are respectively washed once, through rectification under vacuum purifying, obtain target product 3-halo-2, the method for 5-pyrroline compound.
Below in conjunction with specific embodiment, the present invention is described in further detail,
embodiment 1
A kind of 3-halo-2 of preparing, the method for 5-pyrroline compound, the chloro-1-of 3-methyl-2,5-dihydro-1
hpyrroles is example:
The preparation of compound N-methyl-3-pyrrolidone hydrazone:
To one, magnetic agitation is housed, in the 500mL four-hole bottle of thermometer, add 26.72 g(75%, 0.4 mol) hydrazine hydrate, 53 mL ethanol, drip 39 .65g(0.4mol) ethanol (78mL) solution of N-methyl-3-pyrrolidone, 20 ℃～25 ℃ of temperature controls, stir after 2 hours, underpressure distillation goes out ethanol, add 40 mL toluene and continue underpressure distillation solvent, obtain mixture 46.15 g of N-methyl-3-pyrrolidone hydrazone and two N-methyl-3-pyrrolidone hydrazones, in this mixture, add 3.20g(0.1 mol) anhydrous hydrazine, at 90 ℃～100 ℃, stir 2 hours, be down to room temperature, high vacuum (0.095～-0.1MPa) is extracted excessive anhydrous hydrazine out, obtain weak yellow liquid N-methyl-3-pyrrolidone hydrazone 45.30g, yield calculates by 100%.
Compound 3, the preparation of the chloro-1-crassitude of 3-bis-:
In a 1L four-hole bottle that mechanical stirring, thermometer be housed, add 255mL anhydrous methanol, add 255.72g(1.50mol in batches) CuCl
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 75.75g (0.75 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (226mL) solution of 28.29g (0.25 mol) N-methyl-3-pyrrolidone hydrazone, drip and finish, be incubated 8 hours, drip 315g (25%, 2.25 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (200 mL*2), organic layer after merging with 100mL ammonia scrubbing once, 100 mL saturated sodium-chloride water solution washings once, organic layer steams underpressure distillation after solvent, obtains product 26.97g yield 70.05%, purity 96.10%.
Compound 3-chlorin-1-methyl-2,5-dihydro-1
hpyrroles's preparation:
In a 500mL single port bottle that magnetic agitation, prolong be housed, add 53.91g(0.35 mol) 3, the chloro-1-crassitude of 3-bis-, 162mL toluene, 58.57g(0.39 mol) DBU, after reflux 6 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated compound 3-chlorin-1-methyl-2,5-dihydro-1 through rectification under vacuum
hthe chloro-1-of pyrroles and 4-methyl-2,3-dihydro-1
hpyrroles, obtains the chloro-1-of target product 3-methyl-2,5-dihydro-1
hpyrroles 26.10g, GC content: 97.06%, yield 63.42%.
embodiment 2
A kind of 3-halo-2 of preparing, the method for 5-pyrroline compound, the bromo-1-of 3-methyl-2,5-dihydro-1
hpyrroles is example:
Compound 3, the preparation of the bromo-1-crassitude of 3-bis-:
In a 2L four-hole bottle that mechanical stirring, thermometer be housed, add 402mL anhydrous methanol, add 402.05g(1.80mol in batches) CuBr
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 90.90g (0.90 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (272mL) solution of 33.95g (0.30 mol) N-methyl-3-tetramethyleneimine hydrazone, drip and finish, be incubated 6 hours, drip 378g (25%, 2.70 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (240 mL*2), organic layer after merging with 120mL ammonia scrubbing once, once, organic layer steams underpressure distillation after solvent, obtains product 54.57g in 120 mL saturated sodium-chloride water solutions washings, yield 74.88%, purity 96.78%.
The bromo-1-of compound 3-methyl-2,5-dihydro-1
hpyrroles's preparation:
In a 250mL single port bottle that magnetic agitation, prolong be housed, add 48.59g(0.20 mol) 3, the bromo-1-crassitude of 3-bis-, 146mL toluene, 33.47g(0.22 mol) DBU, after reflux 5 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated the bromo-1-of compound 3-methyl-2,5-dihydro-1 through rectification under vacuum
hthe bromo-1-of pyrroles and 4-methyl-2,3-dihydro-1
hpyrroles, obtains the bromo-1-of target product 3-methyl-2,5-dihydro-1
hpyrroles 21.29g, GC content: 97.53%, yield 65.71%.
embodiment 3
A kind of 3-halo-2 of preparing, the method for 5-pyrroline compound, the chloro-1-of 3-benzyl-2,5-dihydro-1
hpyrroles is example:
The preparation of compound N-benzyl-3-pyrrolidone hydrazone:
To one, magnetic agitation is housed, in the 500mL four-hole bottle of thermometer, add 15.35 g(75%, 0.23 mol) hydrazine hydrate, 31mL ethanol, dropping 40.30g(0.23mol) ethanol (80mL) solution of N-benzyl-3-pyrrolidone, 20 ℃～25 ℃ of temperature controls, stir after 2 hours, underpressure distillation goes out ethanol, add 25 mL toluene and continue underpressure distillation solvent, obtain mixture 44.85 g of N-benzyl-3-pyrrolidone hydrazone and two N-benzyl-3-pyrrolidone hydrazones, in this mixture, add 3.68g(0.115 mol) anhydrous hydrazine, at 90 ℃～100 ℃, stir 2 hours, be down to room temperature, high vacuum (0.095～-0.1MPa) is extracted excessive anhydrous hydrazine out, obtain colourless liquid 43.62 g N-benzyl-3-pyrrolidone hydrazones, yield calculates by 100%.
Compound 3, the preparation of the chloro-1-benzyl-pyrrole of 3-bis-alkane:
In a 1L four-hole bottle that mechanical stirring, thermometer be housed, add 317mL anhydrous methanol, add 317.09g(1.86mol in batches) CuCl
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 93.93g (0.93 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (226mL) solution of 58.67g (0.31 mol) N-benzyl-3-pyrrolidone hydrazone, drip and finish, be incubated 8 hours, drip 390.60g (25%, 2.79 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (250 mL*2), organic layer after merging with 120mL ammonia scrubbing once, once, organic layer steams underpressure distillation after solvent, obtains product 51.04g in 120 mL saturated sodium-chloride water solutions washings, yield 71.54%, purity 95.87%.
Compound 3-chlorin-1-benzyl-2,5-dihydro-1
hpyrroles's preparation:
In a 500mL single port bottle that magnetic agitation, prolong be housed, add 41.42g(0.18 mol) 3, the chloro-1-benzyl-pyrrole of 3-bis-alkane, 124mL toluene, 30.12g(0.20 mol) DBU, after reflux 6 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated compound 3-chlorin-1-benzyl-2,5-dihydro-1 through rectification under vacuum
hthe chloro-1-of pyrroles and 4-benzyl-2,3-dihydro-1
hpyrroles, obtains the chloro-1-of target product 3-benzyl-2,5-dihydro-1
hpyrroles 21.83g, GC content: 97.73%, yield 62.62%.
embodiment 4
A kind of 3-halo-2 of preparing, the method for 5-pyrroline compound, the bromo-1-of 3-benzyl-2,5-dihydro-1
hpyrroles is example:
Compound 3, the preparation of the bromo-1-benzyl-pyrrole of 3-bis-alkane:
In a 2L four-hole bottle that mechanical stirring, thermometer be housed, add 201mL anhydrous methanol, add 201.03g(0.90mol in batches) CuBr
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 45.45g (0.45 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (136mL) solution of 28.39g (0.15mol) N-benzyl-3-pyrrolidone hydrazone, drip and finish, be incubated 6 hours, drip 189g (25%, 1.35 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (240 mL*2), organic layer after merging with 60mL ammonia scrubbing once, once, organic layer steams underpressure distillation after solvent, obtains product 35.37g in 60 mL saturated sodium-chloride water solutions washings, yield 73.91%, purity 96.29%.
The bromo-1-of compound 3-benzyl-2,5-dihydro-1
hpyrroles's preparation:
In a 250mL single port bottle that magnetic agitation, prolong be housed, add 76.57g(0.24 mol) 3, the bromo-1-benzyl-pyrrole of 3-bis-alkane, 223mL toluene, 40.16g(0.26 mol) DBU, after reflux 5 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated the bromo-1-of compound 3-benzyl-2,5-dihydro-1 through rectification under vacuum
hthe bromo-1-of pyrroles and 4-benzyl-2,3-dihydro-1
hpyrroles, obtains the bromo-1-of target product 3-benzyl-2,5-dihydro-1
hpyrroles 38.23g, GC content: 97.22%, yield 66.90%.
embodiment 5
A kind of 3-halo-2 of preparing, the method for 5-pyrroline compound, the chloro-1-of 3-tertbutyloxycarbonyl-2,5-dihydro-1
hpyrroles is example:
The preparation of compound 1-tertbutyloxycarbonyl-3-pyrrolidone hydrazone:
To one, magnetic agitation is housed, in the 500mL four-hole bottle of thermometer, add 17.35 g(75%, 0.26 mol) hydrazine hydrate, 35mL ethanol, dropping 48.16g(0.26mol) ethanol (96mL) solution of 1-tertbutyloxycarbonyl-3-pyrrolidone, 20 ℃～25 ℃ of temperature controls, stir after 1 hour, underpressure distillation goes out ethanol, add 35 mL toluene and continue underpressure distillation solvent, obtain mixture 45.92 g of 1-tertbutyloxycarbonyl-3-pyrrolidone hydrazone and two 1-tertbutyloxycarbonyl-3-pyrrolidone hydrazones, in this mixture, add 4.16g(0.13 mol) anhydrous hydrazine, at 90 ℃～100 ℃, stir 2 hours, be down to room temperature, high vacuum (0.095～-0.1MPa) is extracted excessive anhydrous hydrazine out, obtain weak yellow liquid 49.53 g 1-tertbutyloxycarbonyl-3-tetramethyleneimine hydrazones, yield calculates by 100%.
Compound 3, the preparation of the chloro-1-tertbutyloxycarbonyl of 3-bis-tetramethyleneimine:
In a 1L four-hole bottle that mechanical stirring, thermometer be housed, add 307mL anhydrous methanol, add 306.86g(1.80mol in batches) CuCl
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 90.93g (0.90 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (454mL) solution of 59.76g (0.30 mol) 1-tertbutyloxycarbonyl-3-pyrrolidone hydrazone, drip and finish, be incubated 6 hours, drip 378.0g (25%, 2.70 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (250 mL*2), organic layer after merging with 120mL ammonia scrubbing once, once, organic layer steams underpressure distillation after solvent, obtains product 54.62g in 120 mL saturated sodium-chloride water solutions washings, yield 75.82%, purity 96.47%.
Compound 3-chlorin-1-tertbutyloxycarbonyl-2,5-dihydro-1
hpyrroles's preparation:
In a 500mL single port bottle that magnetic agitation, prolong be housed, add 60.03g(0.25 mol) 3, the chloro-1-tertbutyloxycarbonyl of 3-bis-tetramethyleneimine, 180mL toluene, 41.84g(0.275 mol) DBU, after reflux 5 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated compound 3-chlorin-1-tertbutyloxycarbonyl-2,5-dihydro-1 through rectification under vacuum
hthe chloro-1-of pyrroles and 4-tertbutyloxycarbonyl-2,3-dihydro-1
hpyrroles, obtains the chloro-1-of target product 3-tertbutyloxycarbonyl-2,5-dihydro-1
hpyrroles 33.55g, GC content: 97.66%, yield 65.89%.
embodiment 6
Compound 3, the preparation of the bromo-1-tertbutyloxycarbonyl of 3-bis-tetramethyleneimine:
In a 1L four-hole bottle that mechanical stirring, thermometer be housed, add 228mL anhydrous methanol, add 227.83g(1.02mol in batches) CuBr
2, temperature control is less than 10 ℃.In 0 ℃～10 ℃ downhill reaction liquid, drip 51.51g (0.51 mol) Et
3n, drips and finishes, insulated and stirred 30 minutes.In 0 ℃～-10 ℃ downhill reaction liquid, drip anhydrous methanol (271mL) solution of 33.87g (0.17 mol) 1-tertbutyloxycarbonyl-3-pyrrolidone hydrazone, drip and finish, be incubated 4 hours, drip 214.2g (25%, 1.53 mol) ammoniacal liquor, temperature control is less than 30 ℃, toluene extraction (135 mL*2), organic layer after merging with 70mL ammonia scrubbing once, once, organic layer steams underpressure distillation after solvent, obtains product 43.65g in 70 mL saturated sodium-chloride water solutions washings, yield 78.03%, purity 96.95%.
The bromo-1-of compound 3-tertbutyloxycarbonyl-2,5-dihydro-1
hpyrroles's preparation:
In a 500mL single port bottle that magnetic agitation, prolong be housed, add 92.13g(0.28 mol) 3, the bromo-1-tertbutyloxycarbonyl of 3-bis-tetramethyleneimine, 276mL toluene, 46.86g(0.308 mol) DBU, after reflux 4 hours, be down to room temperature, it is 3～4 that reaction solution is washed till pH value with 0.4mol/L HCl hydrochloric acid, and organic layer is used respectively saturated NaHCO
3the aqueous solution and the saturated NaCl aqueous solution are respectively washed once, and organic layer is isolated the bromo-1-of compound 3-tertbutyloxycarbonyl-2,5-dihydro-1 through rectification under vacuum
hthe bromo-1-of pyrroles and 4-tertbutyloxycarbonyl-2,3-dihydro-1
hpyrroles, obtains the bromo-1-of target product 3-tertbutyloxycarbonyl-2,5-dihydro-1
hpyrroles 47.21g, GC content: 97.71%, yield 67.96%.
The above; it is only preferably embodiment of the present invention; but protection scope of the present invention is not limited to this; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; according to technical scheme of the present invention and inventive concept thereof, be equal to replacement or changed, within all should being encompassed in protection scope of the present invention.
Claims (4)
1. logical formula IV 3-halo-2, the preparation method of 5-pyrroline compound, it is characterized in that, by take, to lead to formula I 3-pyrrolidones be raw material, through reacting with hydrazine hydrate and anhydrous hydrazine, generate formula II compound, react with copper halide again and make formula III dihalo product, formula III class dihalo thing and DBU eliminate an one's share of expenses for a joint undertaking hydrogen halide for 2～5 hours in reflux in toluene and generate formula IV compound and formula (V) compound, the ratio of formula IV compound and formula (V) compound is 90:10, R represent methylidene in described general formula, benzyl or tertbutyloxycarbonyl, X represents chlorine atom or bromine atoms,
。
2. logical formula IV 3-according to claim 1 halo-2, the preparation method of 5-pyrroline compound, the mol ratio that it is characterized in that described logical formula I compounds and hydrazine hydrate and anhydrous hydrazine is (1-1.1): (1-1.1): 0.5.
3. logical formula IV 3-according to claim 1 halo-2, the preparation method of 5-pyrroline compound, the mol ratio that it is characterized in that described formula II compounds and copper halide and triethylamine is 1:6:3.
4. logical formula IV 3-according to claim 1 halo-2, the preparation method of 5-pyrroline compound, is characterized in that the mol ratio of described formula III class dihalo thing and DBU is 1:1.0-1.2.
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Citations (2)
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|---|---|---|---|---|
| US4324795A (en) * | 1979-09-25 | 1982-04-13 | Takeda Chemical Industries, Ltd. | Acaricidal agents |
| CN101584694A (en) * | 2009-06-15 | 2009-11-25 | 华东师范大学 | Peptide deformylase inhibitor containing 2, 5-dihydropyrrole and synthesizing method |
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2012
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4324795A (en) * | 1979-09-25 | 1982-04-13 | Takeda Chemical Industries, Ltd. | Acaricidal agents |
| CN101584694A (en) * | 2009-06-15 | 2009-11-25 | 华东师范大学 | Peptide deformylase inhibitor containing 2, 5-dihydropyrrole and synthesizing method |
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| Title |
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| ALKENYL BROMIDES BY BROMINATIVE DEOXYGENATION OF KETONES IN ONE OR TWO STEPS;Ulrich von Roman,deng;《SYNTHESIS》;19931031;第10卷;第985-992页，具体参见第985页scheme1 * |
| Michele Gatti，等.Efficient Ring-Closing Metathesis of Alkenyl Bromides: The Importance of Protecting the Catalyst during the Olefin Approach.《J.AM.CHEM.SOC》.2010,第132卷(第43期),第15179–15181页，具体参见第15180页table2第3行. * |
| Takeda T，等.Oxidation of hydrazones with copper(II) bromide-lithium t-butoxide. A convenient method for the transformation of ketones and aldehydes to gem-dibromides.《SYNLETT》.1996,第3卷第273-274页. * |
| Ulrich von Roman,deng.ALKENYL BROMIDES BY BROMINATIVE DEOXYGENATION OF KETONES IN ONE OR TWO STEPS.《SYNTHESIS》.1993,第10卷第985-992页，具体参见第985页scheme1. * |
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