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CN1724525A - Gamma-butyrolactone derivatives and preparation methods thereof - Google Patents

Gamma-butyrolactone derivatives and preparation methods thereof Download PDF

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CN1724525A
CN1724525A CN 200510043889 CN200510043889A CN1724525A CN 1724525 A CN1724525 A CN 1724525A CN 200510043889 CN200510043889 CN 200510043889 CN 200510043889 A CN200510043889 A CN 200510043889A CN 1724525 A CN1724525 A CN 1724525A
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gamma
butyrolactone
compound
butyl
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赵宝祥
沙磊
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Shandong University
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Shandong University
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Abstract

The invention relates to the gamma- butyrolactone derivative 3-arylmethyl- 5-aryloxymethyl-gamma- butyrolactone of general formula (I). And R1 represents H, C1- 5 alkyl, C1- 5 alkoxy, halogen, nitro or hydroxyl; R2 represents H, C1- 5 alkyl, phenyl, substituted phenyl, naphthyl or substituted naphthyl. The invention also relates to the method for preparation of the compounds, that is, after 3- aryloxy- 1, 2- epoxypropane reacting alpha-arylmethyl diethyl malonate in alkalinity condition, cooling, acidifying, extracting, filtering and pressure-reducing concentrating, the concentrate is finally separated with silica gel column to prepare the product.

Description

Gamma-butyrolactone derivative and preparation method thereof
Technical field
The present invention relates to gamma-butyrolactone derivative and preparation method thereof, relate in particular to 3-arylmethyl-5-aryloxy methyl-gamma-butyrolactone and synthetic, separation thereof, purification process.
Background technology
The butyrolactone structure is the very important structural unit of a class, all contains this structural unit in many natural products and the synthetic drugs.
Butyrolactone derivative has widespread use in the organic synthesis field, be very important intermediate of a class and end product.Now, owing to replace pharmacology and the medicinal property and the economic worth of gamma-butyrolactone derivative, the emphasis that it is still studied for the researchist.The biological activity test of this analog derivative of synthetic shows, that this analog derivative has is antitumor, antiulcer agent, anti-inflammation and sterilization, sedation-analgesia, spasmolytic, inhibition platelet aggregation, suppress effect such as nervus centralis, the tranquillizer that can be used as cell death inducer, anti ulcer agent, antiphlogistic, antithrombotic agent, mental illness treatment, as the clear 63-48270 of patent, JP55020704, IT1255218, related replacement gamma-butyrolactone derivative structure among the GB1602501; Also have a lot of patents to relate in addition and replace gamma-butyrolactone derivative structure and synthetic.Preparation method about this analog derivative comprises: 1) patent No. is halo gamma-butyrolactone and the amino acid ester/aliphatic amide reaction that the patent of EP0151964, EP0144812, US3954760, GB1386205, EP0013542, US4284566 etc. relates to; 2) patent No. is γ-OH/ halo prussiate hydrolysis that the patent of SG2389G, WO2005030747, DE19747226, GB597648, EP0002807, US4200582, US2863878 etc. relates to; 3) to be the haloalkane that relates to of the patent of EP0144812 replace the gamma-butyrolactone reaction with amino to the patent No.; 4) patent No. is that methacrylate derivative and the CO that the patent of GB1086448 relates to carries out carbonylation reaction, hydro-reduction reaction again; 5) patent No. is γ-thiazolinyl carboxylicesters/acid anhydride derivative hydrolysis that the patent of EP0103749, US4190588 relates to; 6) patent No. is gamma-butyrolactone (alkali-metal alkyl oxide or the lithium alkylide) and carboxylicesters reaction in the presence of highly basic that the patent of EP0792877, JP3011046, KR2000052448, US6258963 relates to; 7) patent No. be the patent of CN1362410, US5962700 relate under the catalytic condition of High Temperature High Pressure transition-metal catalyst, alkynes hydrogen and carbon monoxide and hydrogen/water reaction; 8) patent No. is that alkene and butene dioic acid anhydride reactant generate corresponding replaced succinate acid anhydride under the High Temperature High Pressure nitrogen protection that relates to of the patent of JP57075978, EP0046542, uses sodium borohydride reduction again; 9) patent No. be the patent of JP63218669, EP0277562 relate at the nickel-base alloy reaction ax, under High Temperature High Pressure and palladium and the rhenium catalytic condition, water and dioxane mixing solutions are solvent, citric acid and hydrogen reaction; 10) patent No. is that methyl ketone and the glyoxylic ester that the patent of DE19745213 relates to reacts under polyphosphoric acid catalysis; 11) patent No. is that the tetrahydrofuran formic acid under strong acid/diacetyl oxide-acid catalysis that the patent of US6362346 relates to is reset; 12) patent No. is the catalytic hydrogenation reduction levulinic acid ester derivative that the patent of EP0069409, US4420622 relates to; 13) patent No. is the α that the patent of JP57046974 relates to, and behind beta substitution-γ-sulfo-phenoxy group-diethyl malonate hydrolysis decarboxylation, sodium periodate oxidation gained compound carries out Pummerer and resets under diacetyl oxide-acid catalysis.
Preparation method for this analog derivative also comprises: the clear 63-48270 of Japanese Patent relates to the aryloxy propylene oxide and diethyl malonate reacts in the alcoholic solution of sodium alkoxide, generates 3-ethoxycarbonyl-5-aryloxy methyl-gamma-butyrolactone; The patent No. is that epoxyethane derivative and the diethyl malonate that the patent of GB1602501 relates to reacts in the alcoholic solution of sodium alkoxide, sloughs the 3-ethoxycarbonyl by heat again; The patent No. is the epoxyethane derivative that relates to of the patent of JP62277375, US4831166 and alpha-substitution-β-acyl acetic acid ester derivative, and (catalyzer can be alkali metal halide at 20～200 ℃, 1～50bar and catalyst; quaternary amine; season phosphonium salt, alkali metal phosphate or alkaline carbonate) react under the condition.
But, by retrieval: 3, the research of 5-two replacement-gamma-butyrolactone derivatives, particularly 3,5-two replacement-gamma-butyrolactone compounds be the research of 3-arylmethyl-5-aryloxy methyl-gamma-butyrolactone and carry out that this series gamma-butyrolactone is synthetic, the method for separation, purifying, do not appear in the newspapers as yet both at home and abroad at present.
Summary of the invention
At the deficiencies in the prior art, the object of the present invention is to provide a kind of gamma-butyrolactone derivative and preparation method thereof, a kind of 3-arylmethyl-5-aryloxy methyl-gamma-butyrolactone and synthetic, separation thereof, purification process especially are provided.
Gamma-butyrolactone derivative 3-arylmethyl of the present invention-5-aryloxy methyl-gamma-butyrolactone is represented with following general formula (I):
Wherein:
R 1Represent one of the alkyl of straight or branched of hydrogen or 1～5 carbon atom or alkoxy or halogen, nitro, hydroxyl;
R 2Represent alkyl or phenyl, the substituted-phenyl of the straight or branched of hydrogen or 1～5 carbon atom, one of naphthyl, substituted naphthyl.
Specifically, R mentioned above 1Represent methylidene, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl; Adjacent chlorine substituent, to chlorine substituent, adjacent bromine substituent, to bromine substituent, adjacent nitro, to nitro, adjacent hydroxyl, to hydroxyl, adjacent carboxyl, O-methoxy is to one of methoxyl group; R 2Represent methylidene, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl; Phenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, p-nitrophenyl, ortho-nitrophenyl base, p-methoxyphenyl, o-methoxyphenyl; The 1-naphthyl, one of 2-naphthyl.
Wherein, R 1Preferred H, C 1-4Alkyl, C 1～3Alkoxyl group, halogen, nitro, one of hydroxyl; R 2Preferred H, C 1-3Alkyl, phenyl, one of naphthyl.
Wherein, R 1Further preferred H, CH 3, C (CH 3) 3, Cl, Br, NO 2, OCH 3One of; R 2Further preferred H, CH 3, Ph, C 10H 7One of.
Wherein, R 1H most preferably, Cl, NO 2, OCH 3One of; R 2Ph most preferably, C 10H 7One of.
The described compound of above-mentioned general formula (I) expression the preparation method, this method steps is as follows:
Sodium Metal 99.5 added make the pure sodium solution that concentration is 0.1～10mol/L in the proton polar solvent, after treating that the sodium reaction finishes, begin to stir, and under 0 ℃～reflux temperature, it with the mole number ratio 1.0～20: 1 ratio, add concentration successively and be the ethanolic soln of arylmethyl diethyl malonate of 0.5～10mol/L and the ethanolic soln of 3-aryloxy-1,2 epoxy prapane that concentration is 0.5～10mol/L, reacted 1～60 hour, be cooled to 0～15 ℃, add acetic acid and regulate pH to acid, decompression steams solvent, adds the water of 1～10 times of remaining mixture volume, use the chloroform extraction of 1～10 times of water yield again, triplicate merges organic phase, uses 5%NaHCO 3Solution is given a baby a bath on the third day after its birth inferior, wash twice, use anhydrous magnesium sulfate drying, filter concentrating under reduced pressure, enriched material silica gel column chromatography separating purification, used developping agent is a petrol ether/ethyl acetate, its volume ratio is 1～10: 1, or use alcohol crystal, promptly obtain suitable-and anti--3-arylmethyl-5-aryloxy methyl-gamma-butyrolactone mixture;
Wherein, described proton polar solvent is methyl alcohol or ethanol.
Wherein, described arylmethyl diethyl malonate and 3-aryloxy-1,2 epoxy prapane compound mole ratio is preferably 1.0～5.0: 1.
Wherein, preferably 1～24 hour described reaction times.
Wherein, the volume ratio of described developping agent petrol ether/ethyl acetate preferably 1～6: 1.
The reaction formula of the compound of above-mentioned general formula (I) statement is as follows:
Wherein: R in the formula 1, R 2As previously mentioned.
The gamma-butyrolactone derivative 3-arylmethyl-5-aryloxy methyl-gamma-butyrolactone of the present invention preparation can be used as medicine as the tranquillizer of cell death inducer, anti ulcer agent, antiphlogistic, antithrombotic agent, mental illness treatment etc., at antitumor, antiulcer agent, anti-inflammation and sterilization, sedation-analgesia, spasmolytic, inhibition platelet aggregation, suppress aspect such as nervus centralis and have widely and use.
Embodiment
Embodiment 1: suitable-and the preparation of anti--3-benzyl-5-Phenoxymethyl-gamma-butyrolactone
0.229 gram (9.96 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (4 milliliters) solution of 2.503 gram (10.01 mmole) diethyl benzyl malonates then.Be cooled to 37 ℃, add ethanol (2 milliliters) solution of 1.508 gram (10.05 mmole) 3-phenoxy group-1,2 epoxy prapanes.After the back flow reaction 3 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum adds dehydrated alcohol, leaves standstill, and separates out crystal, obtains suitable-and anti--3-benzyl-5-Phenoxymethyl-gamma-butyrolactone mixture (0.366 gram), yield 13%.Structural formula is as follows:
Molecular formula: C 18H 18O 3
Molecular weight: 282
Proterties: white crystal
Fusing point: 61～64 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(600MHz，CDCl 3)(cis∶trans＝67∶33)δ：1.94～1.99(m，1H，CHCHHCH，cis)，2.20～2.23(m，1H，CHCHHCH，trans)，2.32～2.36(m，1H，CHCHHCH，trans)，2.36～2.41(m，1H，CHCHHCH，cis)，2.81～2.87(m，1H，CH 2CH(CO)CH 2)，3.00～3.04(m，1H，CHHC 6H 5，cis)，3.20～3.22(m，1H，CHHC 6H 5，trans)，3.25(dd，1H，J＝4.50?and?J＝13.9CHHC 6H 5，trans)，3.33(dd，1H，J＝4.2?and?J＝14.0?CHHC 6H 5，cis)，4.02～4.04(m，1H，OCHHCH)，4.07(dd，J＝3.9?and?J＝10.4，1H，OCHHCH，cis)，4.13(dd，J＝3.8?and?J＝10.3，1H，OCHHCH，trans)，4.68～4.70(m，1H，OCH 2CH(O)CH 2，trans)，4.70～4.74(m，1H，OCH 2CH(O)CH 2，cis)，6.87～6.89(m，2H，C 6H 2H 3O)，7.23～7.34(m，8H，CH 2C 6H 5?andC 6H 2H 3O)。
Ir data is as follows:
IR(KBr)v：1763，1245，1161，1045cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?282(M +)，207，189，175，157，105，91，77，65，43。
Embodiment 2: suitable-and the preparation of anti--3-benzyl-5-(4-chlorobenzene oxygen methyl)-gamma-butyrolactone
0.231 gram (10.04 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 2.508 gram (10.03 mmole) diethyl benzyl malonates then.Be cooled to 37 ℃, add ethanol (2 milliliters) solution of 1.843 gram (9.99 mmole) 3-(4-chlorophenoxy)-1,2 epoxy prapanes.After the back flow reaction 4 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5% NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum adds dehydrated alcohol, leaves standstill, and separates out crystal, obtains suitable-and anti--3-benzyl-5-(4-chlorobenzene oxygen methyl)-gamma-butyrolactone mixture (0.694 gram), yield 22%.
Structural formula is as follows:
Figure A20051004388900081
Molecular formula: C 18H 17ClO 3
Molecular weight: 316
Proterties: white crystal
Fusing point: 100～103 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝51∶49)δ：1.91～1.96(m，1H，CHCHHCH，cis)，2.15～2.22(m，1H，CHCHHCH，trans)，2.28～2.36(m，1H，CHCHHCH)，2.79～2.86(m，1H，CH 2CH(CO)CH 2)，2.97～3.05(m，1H，CHHC 6H 5，cis)，3.10～3.18(m，1H，CHHC 6H 5，trans)，3.24(dd，1H，J＝4.6?and?J＝13.8?CHHC 6H 5，cis)，3.30(dd，1H，J＝4.3?and?J＝13.9CHHC 6H 5，trans)，3.92～3.98(m，1H，OCHHCH)，4.01(dd，J＝3.7?and?J＝10.5，1H，OCHHCH，trans)，4.07(dd，J＝3.7?and?J＝10.3，1H，OCHHCH，cis)，4.62～4.67(m，1H，OCH 2CH(O)CH 2)，6.78～7.31(m，9H，C 6H 4O?and?C 6H 5)。
Ir data is as follows:
IR(KBr)v：1763，1245，1165，1046cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?316(M +)，281，253，189，168，117，91，77，65，43。
Embodiment 3: suitable-and the preparation of anti--3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolactone
0.235 gram (10.22 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 2.503 gram (10.01 mmole) diethyl benzyl malonates then.Be cooled to 37 ℃, add ethanol (2 milliliters) solution of 1.953 gram (10.02 mmole) 3-(2-nitro-phenoxy)-1,2 epoxy prapanes.55 ℃ of reactions were cooled to below 15 ℃ after 3.5 hours, added 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5% NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum adopts silica gel column chromatography to separate (developping agent is a petrol ether/ethyl acetate=3: 1, volume ratio), obtains suitable-and anti--3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolactone mixture (0.721 gram), yield 22%.
Structural formula is as follows:
Molecular formula: C 18H 17NO 5
Molecular weight: 327
Proterties: yellow liquid
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝46∶54)δ：2.15～2.20(m，1H，CHCHHCH)，2.32～2.42(m，1H，CHCHHCH)，2.80～2.85(m，1H，CH 2CH(CO)CH 2，cis)，2.95～3.05(m，1H，CHHC 6H 5)，3.24～3.37(m，1H，CHHC 6H 5)，4.08～4.15(m，1H，OCHHCH)，4.21(dd，1H，OCHHCH，cis)，4.32(dd，1H，J＝3.0?and?J＝10.3，OCHHCH，trans)，4.67～4.70(m，1H，OCH 2CH(O)CH 2)，7.05～7.86(m，9H，C 6H 4O?and?C 6H 5)。
Ir data is as follows:
IR(film)v：1772，1255，1165，1091?cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?327(M +)，297，281，207，117，105，91，77，65，43。
Embodiment 4: suitable-and the preparation of anti--3-(uncle's 4-fourth benzyl)-5-Phenoxymethyl-gamma-butyrolactone
0.233 gram (10.13 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 2.761 gram (10.00 mmole) uncle's 4-fourth diethyl benzyl malonates then.Be cooled to room temperature, add ethanol (2 milliliters) solution of 1.504 gram (10.03 mmole) 3-phenoxy group-1,2 epoxy prapanes.React after 20 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum adds dehydrated alcohol, leaves standstill, and separates out crystal, obtains suitable-and anti--3-(uncle's 4-fourth benzyl)-5-Phenoxymethyl-gamma-butyrolactone mixture (0.455 gram), yield 14%.
Structural formula is as follows:
Figure A20051004388900101
Molecular formula: C 22H 26O 3
Molecular weight: 338
Proterties: white crystal
Fusing point: 93～95 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝80∶20)δ：1.29(s，9H，C 6H 4C(CH 3) 3，trans)，1.31(s，9H，C 6H 4C(CH 3) 3，cis)，1.92～2.00(m，1H，CHCHHCH，cis)，2.15～2.23(m，1H，CHCHHCH，trans)，2.30～2.34(m，1H，CHCHHCH，trans)，2.35～2.42(m，1H，CHCHHCH，cis)，2.74～2.84(m，1H，CH 2CH(CO)CH 2，)，2.95～3.03(m，1H，CHHC 6H 4，cis)，3.15～3.21(m，2H，CH 2C 6H 4，trans)，3.27(dd，1H，J＝4.1?and?J＝14.0，CHHC 6H 4，cis)，3.98～4.04(m，1H，OCHHCH)，4.06(dd，J＝3.9?and?J＝10.4，1H，OCHHCH，cis)，4.10(dd，1H，J＝3.8?and?J＝10.3，OCHHCH，trans)，4.66～4.72(m，1H，OCH 2CH(O)CH 2)，6.85～7.32(m，8H，C 6H 4O?and?C 6H 4(CH 3) 3)。
Ir data is as follows:
1R(KBr)v：1769，1236，1161.，1051cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?338(M +)，323，281，204，189，134，117，105，91，77，57。
Embodiment 5: suitable-and the preparation of anti--3-menaphthyl-5-Phenoxymethyl-gamma-butyrolactone
0.258 gram (11.22 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 3.000 gram (10.00 mmole) menaphthyl diethyl malonates then.Be cooled to room temperature, add ethanol (2 milliliters) solution of 1.524 gram (10.16 mmole) 3-phenoxy group-1,2 epoxy prapanes.Behind the room temperature reaction 24 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum separate to be purified by (developping agent be petrol ether/ethyl acetate=6: 1) with silica gel column chromatography, obtains suitable-and anti--3-menaphthyl-5-Phenoxymethyl-gamma-butyrolactone mixture (1.100 gram), yield 33%.
Structural formula is as follows:
Figure A20051004388900111
Molecular formula: C 22H 20O 3
Molecular weight: 332
Proterties: white crystal
Fusing point: 116～119 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝35∶65)δ：2.19～2.28(m，2H，CHCH 2CH)，2.99～3.09(m，1H，CH 2CH(CO)CH 2)，3.13～3.21(m，1H，CHHC 10H 7，trans)，3.33～3.41(m，1H，CHHC 10H 7，cis)，3.91～3.99(m，1H，CHHC 10H 7)，3.99～4.10(m，1H，OCH 2CH，cis)，4.04(dd，J＝4.80?and?J＝9.62，1H，OCHHCH，trans)，4.12(dd，J＝3.8?and?J＝10.6，1H，OCHHCH，trans)，4.63～4.68(m，1H，OCH 2CH(O)CH 2，trans)，4.77～4.80(m，1H，OCH 2CH(O)CH 2，cis)，6.80～8.08(m，12H，C 6H 5O?and?C 10H 7)。
Ir data is as follows:
IR(KBr)v：1764，1239，1161，1073cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?332(M +)，239，141，94，77，65。
Embodiment is 6 suitable-and the preparation of anti--3-menaphthyl-5-(4-chlorobenzene oxygen methyl)-gamma-butyrolactone
0.233 gram (11.13 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 3.049 gram (10.16 mmole) menaphthyl diethyl malonates then.Be cooled to room temperature, add ethanol (2 milliliters) solution of 1.846 gram (10.01 mmole) 3-(4-chlorophenoxy)-1,2 epoxy prapanes.Behind the room temperature reaction 24 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum separate to be purified by (developping agent be petrol ether/ethyl acetate=3: 1) with silica gel column chromatography, obtains suitable-and anti--3-menaphthyl-5-(4-chlorobenzene oxygen methyl)-gamma-butyrolactone mixture (1.506 gram), yield 42%.
Structural formula is as follows:
Figure A20051004388900121
Molecular formula: C 22H 19ClO 3
Molecular weight: 366
Proterties: white crystal
Fusing point: 147～151 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝80∶20)δ：1.94～1.98(m，1H，CHCHHCH，trans)，2.18～2.24(m，2H，CHCH 2CH，cis?and?1H，CHCHHCH，trans)，2.99～3.08(m，1H，CH 2CH(CO)CH 2)，3.19～3.20(m，1H，CHHC 10H 7，trans)，3.30～3.37(m，1H，CHHC 10H 7，cis)，3.90～3.95(m，2H，CHHC 10H 7?and?OCHHCH，cis)，3.90～4.02(m，3H，CHHC 10H 7?andOCHHCH，trans)，4.06～4.10(m，2H，OCHHCH，trans)，4.09(dd，J＝3.7?and?J＝10.4，1H，OCHHCH，cis)，4.63～4.65(m，1H，OCH 2CH(O)CH 2，trans)，4.74～4.79(m，1H，OCH 2CH(O)CH 2，cis)，6.71～8.08(m，11H，C 6H 4O?and?C 10H 7)。
Ir data is as follows:
IR(KBr)v：1764，1242，1154，1052cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?366(M +)，349，239，221，195，183，179，167。
Embodiment 7: the preparation of suitable-3-menaphthyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolactone
0.101 gram (5.439 mmole) sodium Metal 99.5 is added in 5 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (1 milliliter) solution of 1.673 gram (5.60 mmole) menaphthyl diethyl malonates then.Be cooled to room temperature, add ethanol (1.5 milliliters) solution of 0.203 gram (1.04 mmole) 3-(2-nitro-phenoxy)-1,2 epoxy prapane.Behind the room temperature reaction 24 hours, be cooled to below 15 ℃, add 0.4 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum separate to be purified by (developping agent be petrol ether/ethyl acetate=2: 1) with silica gel column chromatography, obtains suitable-3-menaphthyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolactone mixture (0.317 gram), yield 81%.
Structural formula is as follows:
Figure A20051004388900131
Molecular formula: C 22H 19NO 5
Molecular weight: 377
Proterties: light yellow crystal
Fusing point: 157～159 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)δ：2.17～2.32(m，2H，CHCH 2CH)，3.01～3.07(m，1H，CH 2CH(CO)CH 2)，3.52～3.64(m，1H，CHHC 10H 7)，3.92(dd，1H，J＝4.3?and?J＝14.4CHHC 10H 7)，4.07(dd，J＝2.9?and?J＝10.2，1H，OCHHCH)，4.26(dd，J＝3.3?and?J＝10.2，1H，OCHHCH)，4.76～4.80(m，1H，OCH 2CH(O)CH 2)，7.00～8.03(m，11H，C 6H 4O?andC 10H 7)。
Ir data is as follows:
IR(KBr)v：1765，1264，1171cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?377(M +)，300，226，191，181，153，141。
Embodiment 8: suitable-and the preparation of anti--3-menaphthyl-5-(2-methoxyl group Phenoxymethyl)-gamma-butyrolactone
0.256 gram (11.13 mmole) sodium Metal 99.5 is added in 10 milliliters of dehydrated alcohols, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 3.015 gram (11.00 mmole) menaphthyl diethyl malonates then.Be cooled to room temperature, add ethanol (2 milliliters) solution of 1.181 gram (10.10 mmole) 3-(2-methoxyl group phenoxy group)-1,2 epoxy prapanes.Behind the room temperature reaction 24 hours, be cooled to below 15 ℃, add 1 milliliter of acetic acid.Decompression steams ethanol, and residuum adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic phase, use 5%NaHCO 3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residuum separate to be purified by (developping agent be petrol ether/ethyl acetate=3: 1) with silica gel column chromatography, obtains suitable-and anti--3-menaphthyl-5-(2-methoxyl group Phenoxymethyl)-gamma-butyrolactone mixture (1.774 gram), yield 49%.
Structural formula is as follows:
Figure A20051004388900141
Molecular formula: C 23H 22O 4
Molecular weight: 362
Proterties: white crystal
Fusing point: 112～116 ℃
The nuclear magnetic resonance spectrum data are as follows:
1H?NMR(400MHz，CDCl 3)(cis∶trans＝10∶90)δ：2.02～2.10(m，1H，CHCHHCH)，2.22～2.29(m，1H，CHCHHCH)，2.90～3.05(m，1H，CH 2CH(CO)CH 2，cis)，3.11～3.18(m，2H，CH 2CH(CO)CH 2?and?CHHC 10H 7，trans)，3.11～3.18(m，1H，CHHC 10H 7，cis)，3.63(s，3H，OCH 3，cis)，3.83(s，3H，OCH 3，trans)，3.97～4.00(m，1H，CHHC 10H 7)，4.09～4.21(m，2H，OCH 2CH，cis)，4.11(dd，J＝4.7?and?J＝10.9，1H，OCHHCH，trans)，4.19(dd，J＝3.6?and?J＝10.8，1H，OCHHCH，trans)，4.69～4.71(m，1H，OCH 2CH(O)CH 2，trans)，4.72～4.80(m，1H，OCH 2CH(O)CH 2，cis)，6.92～8.09(m，11H，C 6H 4O?and?C 10H 7)。
Ir data is as follows:
IR(KBr)v：1762，1259，1156，1051cm -1。
Mass-spectrometric data is as follows:
Ms，m/z?362(M +)，345，239，221，195，193，183，179，163。

Claims (9)

1.下述通式(I)的化合物：1. The compound of following general formula (I):
Figure A2005100438890002C1
Figure A2005100438890002C1
 其中：in: R1代表氢或1～5个碳原子的直链或支链的烷基或烷氧基或卤素、硝基、羟基之一；R 1 represents hydrogen or one of linear or branched alkyl or alkoxy groups of 1 to 5 carbon atoms, or halogen, nitro, or hydroxyl; R2代表氢或1～5个碳原子的直链或支链的烷基或苯基、取代苯基，萘基、取代萘基之一。R 2 represents one of hydrogen or straight-chain or branched-chain alkyl or phenyl, substituted phenyl, naphthyl, or substituted naphthyl with 1 to 5 carbon atoms. 2.按照权利要求1所述的化合物，其中：2. The compound according to claim 1, wherein: R1代表甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基；邻氯取代基，对氯取代基，邻溴取代基，对溴取代基，邻硝基，对硝基，邻羟基，对羟基，邻羧基，邻甲氧基，对甲氧基之一；R 1 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl; o-chloro substituent, para-chloro substituent, o-bromo Substituent, p-bromo substituent, one of o-nitro, p-nitro, o-hydroxyl, p-hydroxyl, o-carboxyl, o-methoxy, p-methoxy; R2代表甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基；苯基、对氯苯基、邻氯苯基、对溴苯基、邻溴苯基、对硝基苯基、邻硝基苯基、对甲氧基苯基、邻甲氧基苯基；1-萘基，2-萘基之一。R 2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl; phenyl, p-chlorophenyl, o-chlorophenyl , p-bromophenyl, o-bromophenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl, o-methoxyphenyl; 1-naphthyl, one of 2-naphthyl. 3.按照权利要求1所述的化合物，其中R1代表H，C1-4烷基，C1～3烷氧基，卤素，硝基，羟基之一；R2代表H，C1～3烷基，苯基，萘基之一。3. The compound according to claim 1, wherein R 1 represents one of H, C 1-4 alkyl, C 1～3 alkoxy, halogen, nitro, hydroxyl; R 2 represents H, C 1～3 One of alkyl, phenyl, naphthyl. 4.按照权利要求3所述的化合物，其中R1代表H，CH3，C(CH3)3，Cl，Br，NO2，OCH3之一；R2代表H，CH3，Ph，C10H7之一。4. The compound according to claim 3, wherein R 1 represents one of H, CH 3 , C(CH 3 ) 3 , Cl, Br, NO 2 , OCH 3 ; R 2 represents H, CH 3 , Ph, C 10 H 7 one. 5.按照权利要求4所述的化合物，其中R1代表H，Cl，NO2，OCH3之一；R2代表Ph，C10H7之一。5. The compound according to claim 4, wherein R 1 represents one of H, Cl, NO 2 , OCH 3 ; R 2 represents one of Ph, C 10 H 7 . 6.权利要求1～5之一所述的化合物的制备方法，该方法步骤如下：6. The preparation method of the compound described in one of claims 1 to 5, the method steps are as follows: 将金属钠加入质子极性溶剂中制得浓度为0.1～10mol/L的醇钠溶液，待钠反应完毕后，开始搅拌，并在0℃～回流温度下，以摩尔数比例为1.0～20∶1的比例，依次加入浓度为0.5～10mol/L的芳甲基丙二酸二乙酯的乙醇溶液和浓度为0.5～10mol/L的3-芳氧基-1，2-环氧丙烷的乙醇溶液，反应1～60小时，冷却至0～15℃，加入醋酸调节pH至酸性，减压蒸出溶剂，加入剩余混合物体积量1～10倍的水，再用1～10倍水量的氯仿萃取，重复三次，合并有机相，用5％NaHCO3溶液洗三次，水洗两次，用无水硫酸镁干燥，过滤，减压浓缩，浓缩物用硅胶柱层析分离纯化，所用展开剂为石油醚/乙酸乙酯，其体积比是1～10∶1；或用乙醇结晶；即得到顺-和反-3-芳甲基-5-芳氧甲基-γ-丁内酯混合物；Add metal sodium into a proton polar solvent to prepare a sodium alkoxide solution with a concentration of 0.1 to 10 mol/L. After the sodium reaction is complete, start stirring, and at 0°C to reflux temperature, the molar ratio is 1.0 to 20: 1 ratio, sequentially add the ethanol solution of diethyl arylmethylmalonate with a concentration of 0.5-10mol/L and the ethanol solution of 3-aryloxy-1,2-epoxypropane with a concentration of 0.5-10mol/L Solution, react for 1-60 hours, cool to 0-15°C, add acetic acid to adjust the pH to acidic, distill off the solvent under reduced pressure, add water 1-10 times the volume of the remaining mixture, and extract with chloroform 1-10 times the volume of water , repeated three times, combined organic phases, washed three times with 5% NaHCO3 solution, washed twice with water, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, the concentrate was separated and purified by silica gel column chromatography, and the developing agent used was petroleum ether / ethyl acetate, its volume ratio is 1～10: 1; Or crystallization with ethanol; That is to obtain cis-and trans-3-arylmethyl-5-aryloxymethyl-γ-butyrolactone mixture; 其中，所述质子极性溶剂是甲醇或乙醇。Wherein, the protic polar solvent is methanol or ethanol. 7.如权利要求6所述的化合物的制备方法，其特征是，所述的芳甲基丙二酸二乙酯与3-芳氧基-1，2-环氧丙烷化合物摩尔数比为1.0～5.0∶1。7. the preparation method of compound as claimed in claim 6 is characterized in that, described arylmethyl malonate diethyl ester and 3-aryloxy-1,2-propylene oxide compound molar ratio are 1.0 ~5.0:1. 8.如权利要求6所述的化合物的制备方法，其特征是，所述的反应时间是1～24小时。8. The preparation method of the compound as claimed in claim 6, characterized in that, the reaction time is 1-24 hours. 9.如权利要求6所述的化合物的制备方法，其特征是，所述展开剂石油醚/乙酸乙酯的体积比是1～6∶1。9. The preparation method of the compound as claimed in claim 6, characterized in that, the volume ratio of the developer petroleum ether/ethyl acetate is 1-6:1.
CN 200510043889 2005-06-24 2005-06-24 Gamma-butyrolactone derivatives and preparation methods thereof Pending CN1724525A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100387232C (en) * 2006-03-21 2008-05-14 山东大学 Pharmaceutical use of 3-benzyl-5-(2-nitrophenoxymethyl)-γ-butyrolactone
WO2008061400A1 (en) * 2006-11-23 2008-05-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Fatty acid synthase inhibitors and medical uses thereof
CN112759566A (en) * 2020-12-31 2021-05-07 江苏兄弟维生素有限公司 Application of liquid sodium methoxide in synthesis of alpha-acetyl-gamma-butyrolactone and synthesis method of alpha-acetyl-gamma-butyrolactone

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100387232C (en) * 2006-03-21 2008-05-14 山东大学 Pharmaceutical use of 3-benzyl-5-(2-nitrophenoxymethyl)-γ-butyrolactone
WO2008061400A1 (en) * 2006-11-23 2008-05-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Fatty acid synthase inhibitors and medical uses thereof
CN112759566A (en) * 2020-12-31 2021-05-07 江苏兄弟维生素有限公司 Application of liquid sodium methoxide in synthesis of alpha-acetyl-gamma-butyrolactone and synthesis method of alpha-acetyl-gamma-butyrolactone
CN112759566B (en) * 2020-12-31 2023-05-02 江苏兄弟维生素有限公司 Application of liquid sodium methoxide in synthesis of alpha-acetyl-gamma-butyrolactone and synthesis method of alpha-acetyl-gamma-butyrolactone

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