CN1273245A - Gamma-butenolide containing aryl substituent at beta position and its solid-phase synthesis process - Google Patents
Gamma-butenolide containing aryl substituent at beta position and its solid-phase synthesis process Download PDFInfo
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- CN1273245A CN1273245A CN 00115358 CN00115358A CN1273245A CN 1273245 A CN1273245 A CN 1273245A CN 00115358 CN00115358 CN 00115358 CN 00115358 A CN00115358 A CN 00115358A CN 1273245 A CN1273245 A CN 1273245A
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Abstract
A solid-phase synthesis process for preparing gamma-butdnolide containing aryl substitutent at beta position includes coupling the alkyl, carboxyl and ester substituted aryl iodione or bromine to resin in organic solvent under the existence of alkali, cyclizing reaction with relative R2C=C=C(R')COOH under catalysis of Pd to obtain solid-phase carried gamma-butenolide containing aryl substituent at beta position, and eluting the gamma-butenolide from the high polymer as carrier with high output rate and purity under existence of Lewis acid to obtain the gamma-butenolide containing aryl substituent at beta position. It can be used for medicines or agricultural chemicals with low cost.
Description
The present invention relates to a kind of β position and contain the five-membered ring unsaturated lactone and the synthetic method thereof of aryl substituent, i.e. γ-butenolide and solid-phase synthesis thereof.
Five Yuans unsaturated lactone rings are one of modal structure components in the natural product, have multiple important physical activity.For example, antisepsis and anti-inflammation, antimycotic, antitumor, and regulate seed germination and plant-growth etc., at aspects such as medicine and agricultural chemicals huge value of exploiting and utilizing is arranged.For a long time, people are imagining library of molecules how to set up this compounds always, thereby systematically carry out bioactive screening.And the β position is contained the γ-butenolide of aryl substituent and is had its unique physiologically active, how easy and synthetic efficiently this compounds? but the traditional synthetic method of γ-butenolide all is based on the alternate reaction of solution, for example, (1) document T.L.1987,28, the method of the reaction of the metal carbonylcomplex of report and alkynes in 2233 and Chem.Commun.1987,649; (2) document Synthesis1987, the synthesis method that lactonizes of the 3-hydroxyl-1-olefinic carboxylic acid of report in 389; (3) document Organometallics 1988,7, selective reduction method (4) the document J.O.C.1988 of the cyclic acid anhydride of report in 1013, the zone of the report furans method that replaces of oxidation selectively in 53,2773.; (5) document J.O.C.1996, in 61,3238. under the palladium catalysis of report, 3-iodo-2 (Z)-vinylcarbinol carbonyl lactonization reaction synthetic method; (6) document J.O.C.1997, the carbonyl cyclization of the catalytic 2-alkynol of zeroth order palladium of report in 62,5684. and J.O.C.1997,62,3422; (7) document T.L.1989, the free radical cyclization of 2 '-bromo alkyl acetylenic acid ester of report in 30,7469; (8) document T.L.1985, report at Ag in 26,4811
+Or electrophilic reagent induces down, 2,3-di-olefin(e) acid have the ring reaction of one's own; (9) document J.O.C.1995, in 60,796 under the zeroth order palladium catalysis of report, 2, the coupled cyclization of 3-di-olefin(e) acid and aryl halide.(10) bright, the Wu Shulin of Taro Aso etc. in patent 99119945.6, disclose by copper halide and cuprous halide participate in 2, the method of the synthetic beta-halobutenolide of 3-di-olefin(e) acid cyclization, the butenolide compound that synthesizes some physiologically active for cheap highly selective provides real approach.However, tentatively do not put forward some method and will use expensive reagent, some has provided unfavorable productive rate, even they may be effective for synthetic certain or several compounds, but want to be had in a large number easily rapidly the different compounds of precursor structure, but being time-consuming, almost is impossible.
Purpose of the present invention just provides γ-butenolide that aryl substituent is contained in a class β position, and its general molecular formula is as follows:
R wherein
1, R
2,=H, alkyl, wherein alkyl is C
nH
2n+1, n=1-7, R
3, R
4=H, alkyl, ester group, carboxyl, acetyl-o-methyl, wherein alkyl is C
nH
2n+1, n=1-7.
Another object of the present invention just provides the corresponding synthetic method of this type of compound, promptly in organic solvent, contain 2 of corresponding group, 3-joins olefin(e) acid, with contain the halid resin of corresponding aryl substituent, under the catalysis of alkali and palladium catalyst, react, obtain γ-butenolide that aryl substituent is contained in corresponding resin-carried β position; In the presence of Lewis acid,, obtain γ-butenolide that aryl substituent is contained in the β position again by the organic solvent wash-out.Reaction equation:
Wherein X=Br, I; R
1, R
2,=H, alkyl, wherein alkyl is C
nH
2n+1, n=1-7; R
3, R
4=H, alkyl, ester group, carboxyl, acetyl-o-methyl, wherein alkyl is C
nH
2n+1, n=1-7.
Concrete reactions steps is as follows:
(1) it is halid resin-carried to contain corresponding aryl substituent: at organic solvent
In, contain corresponding aryl substituent halogenide, at the bar of alkali, 60-100 ℃
Part descends and resin reaction 12-24 hour, can will contain corresponding aryl substituent
Halogenide loads on the resin, and recommended temperature is 80 ℃;
(2) the β position of synthetic resins load is contained in the γ-butenoic acid of aryl substituent
Ester: under palladium catalysis, resin-carried contain corresponding aryl substituent halogenide with
Corresponding di-olefin(e) acid R
2C=C=C (R
1) COOH exists at 60-80 ℃ and alkali
Under the condition, reacted 72-96 hour, annulation takes place, thereby obtain tree
γ-the butenolide of aryl substituent is contained in the β position of fat load, recommends temperature
Degree is 70 ℃;
(3) resin elution gets γ-butenolide that aryl substituent is contained in the β position:
Lewis acid exists down, with resin-carried β position contain the γ of aryl substituent-
Butenolide adds in the organic solvent, and stirring at room 2-12 hour, high yield
Rate, high purity obtain γ-butenolide that aryl substituent is contained in the β position.
Wherein resin is Merrifield resin, Wary resin, Rink resin, and organic solvent comprises CH
3CN, THF, DMF, DMA, toluene etc.; Alkali comprises salt of wormwood/sodium/caesium, potassium tert.-butoxide/sodium, diisopropyl ethyl amine, triethylamine etc., the consumption 4-8 equivalent of alkali;
2,3-connection olefin(e) acid needs the 2-6 equivalent usually, and palladium catalyst is a tetrakis triphenylphosphine palladium, Pd
2(dba)
3CHCl
3/ PPh
3, Pd (OAc)
2/ PPh
3, PdCl
2/ PPh
3Alkali wherein: 2,3-joins olefin(e) acid=2-4: 1; The palladium catalyst consumption is 10%-30%; Wherein 2,3-joins olefin(e) acid: the aryl halide of polymer-supported: palladium catalyst=4: 1: 0.1;
Lewis acid comprises FeCl
3, ZnCl
2, AlCl
3, ZnBr
2, SnCl
4, TiCl
4, ZrCl
4, its consumption is the 3-10 equivalent.
The present invention compares with existing synthetic method, has following characteristics:
1. use excessive connection olefin(e) acid, reaction yield is improved greatly, be higher than the solution phase
Productive rate;
2. operation, especially separation and purification have been simplified greatly.Only need through simply
Filter, wash, the purity of crude product just can reach about 90%;
All feed intake and aftertreatment all very similar, be easy to automatization;
4. used cheap Merrifield resin and some alkali and inorganic salt commonly used,
Wherein inorganic salt are as Lewis acid, and are with low cost, and good prospects for application is arranged.
Following examples help to understand the present invention, but are not limited to content of the present invention:
Embodiment 1
2.0-2.5 milliequivalent/gram Merrifield resin is joined among 80 milliliters of DMF, and stirring at room adds 1.5 equivalent 4-Iodobenzoic acids after 10 minutes successively, and 3.0 normal salt of wormwood are warmed up to 80 ℃, stirs 18 hours.Be chilled to room temperature then, filter, use 20 milliliters of DMF successively, 20 milliliters of DMF/H
2O, 20 milliliters of H
2O, 20 milliliters of DMF, 20 milliliters of MeOH washing resins, vacuum-drying is spent the night, and obtains resin-carried 4-Iodobenzoic acid ester 4.12 grams, productive rate 93%.
The resin of 1.64 milliequivalents/gram above-mentioned steps preparation is joined in 4 milliliters of anhydrous acetonitriles; under nitrogen protection, add 4.0 equivalents 2 successively; 3-diene undeeanoic acid, 8.0 equivalent diisopropyl ethyl amines and 15mol% tetrakis triphenylphosphine palladium, reaction is three days under 70 ℃ of conditions.Be chilled to room temperature then, filter, use 5 milliliters of DMF successively, 5 milliliters of DMF/H2O, 5 milliliters of H2O, 5 milliliters of DMF, 5 milliliters of THF, 10 milliliters of MeOH washing resins, vacuum-drying is spent the night, and obtains 101 milligrams of resin-carried γ-butenolides, productive rate ~ 100%.
With the resin of 1.50 milliequivalents/gram step 2 preparation join expanded 30 minutes in 2 milliliters of methylene dichloride after, be chilled to 0 ℃ with ice-water bath.The 0.3 mol Nitromethane 99Min. liquid that will contain 0.6 equivalent aluminum trichloride (anhydrous) joins rapidly in the above-mentioned system, and 0 ℃ was stirred 30 minutes down, filters.With ethyl acetate washing resin three times, filtrate is transferred in the separating funnel, with 0.5N hydrochloric acid soln washed twice.The aqueous solution merges organic phase with ethyl acetate extraction three times, and drying is concentrated into driedly, obtains 30 milligrams of products
5-n-heptyl-4-(4 '-hydroxyl carbon back benzene)-2 (5 hydrogen)-furanone: yield 99%, purity 93%, solid.
1H NMR (300MHz, CD
3COCD
3) δ 8.18 (d, J=8.4Hz, 2H), 7.90 (d, J=8.4Hz, 2H), 6.66 (s, 1H), 5.84 (dt, J=5.9,1.5Hz, 1H), 1.27-1.75 (m, 12H), 0.91 (t, J=7.0Hz, 3H); MS (m/e) 303 (M
++ 1,26), 302 (M
+, 27), 204 (100); HRMS calcd.for C
18H
22O
4:
302.1512，
found?302.1507.
Embodiment 2
2.5 milliequivalents/gram Merrifield resin is joined among 80 milliliters of DMF, and stirring at room adds 1.5 equivalent parabromobenzoic acids after 10 minutes successively, and 3.0 normal yellow soda ash are warmed up to 70 ℃, stirs 20 hours.Be chilled to room temperature then, filter, use 20 milliliters of DMF successively, 20 milliliters of DMF/H
2O, 20 milliliters of H
2O, 20 milliliters of DMF, 20 milliliters of MeOH washing resins, vacuum-drying is spent the night, and obtains resin-carried parabromobenzoic acid ester, productive rate 93%.
The resin of 1.64 milliequivalents/gram above-mentioned steps preparation is joined in 4 milliliters of anhydrous acetonitriles, add 4.0 equivalents 2 successively under nitrogen protection, the 3-diene is sad, 8.0 equivalent triethylamine and 20mol%Pd
2(dba)
3CHCl
3/ PPh
3, reaction is three days under 70 ℃ of conditions.Be chilled to room temperature then, filter, use 5 milliliters of DMF successively, 5 milliliters of DMF/H2O, 5 milliliters of H2O, 5 milliliters of DMF, 5 milliliters of THF, 10 milliliters of MeOH washing resins, vacuum-drying is spent the night, and obtains resin-carried γ-butenolide, productive rate ~ 100%.
With the resin of 1.50 milliequivalents/gram step 2 preparation join expanded 30 minutes in 2 milliliters of methylene dichloride after, be chilled to 0 ℃ with ice-water bath.To contain the anhydrous ZnCl of 0.6 equivalent
20.3 mol Nitromethane 99Min. liquid join rapidly in the above-mentioned system, 0 ℃ was stirred 30 minutes down, filters.With ethyl acetate washing resin three times, filtrate is transferred in the separating funnel, with 0.5N hydrochloric acid soln washed twice.The aqueous solution merges organic phase with ethyl acetate extraction three times, and drying is concentrated into driedly, obtains product
5-n-hexyl-4-(4 '-hydroxycarbonyl group benzene)-2 (5 hydrogen)-furanone: yield 93%, purity 95%, solid.
1H NMR (300MHz, CD
3COCD
3) δ 8.20 (d, J=8.5Hz, 2H), 7.87 (d, J=8.5Hz, 2H), 6.63 (d, J=1.5Hz, 1H), 5.81 (dt, J=7.5,1.5Hz, 1H), 1.54-1.71 (m, 1H), 1.25-1.41 (m, 5H), 0.89 (t, J=7.0Hz, 3H); MS (m/e) 261 (M
++ 1,19), 260 (M
+, 12), 204 (100); HRMS calcd.for C
15H
16O
4:
260.1044，
found?260.1051.
Embodiment 3
Reactions steps is with embodiment 1, and different is that the used resin of step 1 is the wary resin, and alkali is 4.0 normal potassium tert.-butoxides, and temperature is 90 ℃; Step 2 organic solvent is DMA, and 6.0 equivalents 2,3-diene capric acid, 6.0 normal yellow soda ash, palladium catalyst are the Pd (OAc) of 25mol%d
2/ PPh
3, temperature of reaction is 80 ℃; Lewis acid is 0.4 normal FeCl
3Product is:
5-cyclohexyl-4-(4 '-hydroxycarbonyl group benzene)-2 (5 hydrogen)-furanone: yield ~ 100%, purity 94%, solid,
1H NMR (400MHz, CD3COCD3) δ 8.15 (d, J=8.4Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 6.57 (brs, 1H), 5.75 (brs, 1H), 0.80-2.00 (m, 11H); MS (m/e) 286 (M
+, 4), 204 (100); HRMS calcd.for C
17H
18O
4:
286.1200，
found?286.1188.
Embodiment 4
Reactions steps is with embodiment 2, and different is that the used resin of step 1 is the Link resin, and alkali is 4.0 normal cesium carbonates, and temperature is 60 ℃; Step 2 organic solvent is THF, 3.0 equivalent 2-methyl-2, and 3-diene capric acid, 6.0 normal triethylamines, palladium catalyst are the PdCl of 10mol%d
2/ PPh
3, temperature of reaction is 70 ℃; Lewis acid is 0.2 normal SnCl
4Product is:
5-n-hexyl-4-(4 '-hydroxycarbonyl group benzene)-3-methyl-2 (5 hydrogen)-furanone: yield 84%, purity 85%, solid.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.3Hz, 2H), 7.36 (d, J=8.3Hz, 2H), 5.27-5.32 (m, 1H), 1.99 (s, 3H), 1.63-1.78 (m, 1H), 1.18-1.33 (m, 9H), 0.80 (t, J=6.8Hz, 3H); MS (m/e) 302 (M
+, 10), 115 (100); HRMS calcd.for C
18H
22O
4
302.1512，
found?302.1496.
Embodiment 5
Reactions steps is with embodiment 2, the different halogenide that step 1 added be o-iodobenzoic acid, alkali is 6.0 normal sodium tert-butoxides, temperature is 80 ℃; Step 2 organic solvent is a toluene, and 6.0 normal triethylamines, palladium catalyst are the PdCl of 30mol%d
2/ PPh
3, temperature of reaction is 60 ℃; Lewis acid is 0.6 normal TiCl
4, product is:
5-n-heptyl-4-(2 '-hydroxycarbonyl group benzene)-2 (5 hydrogen)-furanones: yield 100%.purity 90%, oil.
1H NMR (300MHz, CD3COCD3) δ 8.04 (d, J=7.2Hz, 1H), 7.73 (t, J=7.5Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 7.49 (d, J=7.2Hz, 1H), 6.12 (s, 1H), 5.57 (m, 1H), 1.15-1.69 (m, 12H), 0.86 (t, J=6.5Hz, 3H); MS (m/e) 302 (M
+, 6), 146 (100); HRMS calcd.for C
18H
22O
4
302.1512，
found?302.1513.
Embodiment 6
Reactions steps is with embodiment 5, and different is that step 2 organic solvent is THF, 6.0 equivalents 2, and the acid of 3-diene isodecyl, 4.0 normal triethylamines, palladium catalyst are the PdCl of 10mol%d
2/ PPh
3, Lewis acid is 0.4 normal ZrCl
4, product is:
5-cyclohexyl-4-(2 '-hydroxycarbonyl group benzene)-2 (5 hydrogen)-furanone: yield ~ 100%, purity 96%, solid.
1H NMR (400MHz, CD3COCD3) δ 8.06 (dd, J=7.5,1.0Hz, 1H), 7.70-7.87 (m, 1H), 7.54-7.69 (m, 1H), 7.45 (dd, J=7.5,1.0Hz, 1H), 6.14 (d, J=1.7Hz, 1H), 5.50 (m, 1H), 0.85-1.70 (m, 11H); MS (m/e) 286 (M
+, 5), 146 (100); HRMS calcd.for C
17H
18O
4
286.1200，
found?286.1223.
Embodiment 7
Reactions steps is with embodiment 5, the different halogenide that step 1 added for to the acetoxyl group bromobenzene, product is:
4-(4 '-acetyloxy phenyl)-5-(n-heptyl)-2 (5 hydrogen)-furanone: yield 89%, purity 94%, oil.
1H NMR (300MHz, CDCl3) δ 7.47 (d, J=7.9Hz, 2H), 7.22 (d, J=7.9Hz, 2H), 6.28 (s, 1H), 5.47 (d, J=5.9Hz, 1H), 2.38 (s, 3H), 1.91-2.10 (m, 1H), 1.35-1.43 (m, 11H), 0.86 (t, J=6.8Hz, 3H); MS (m/e) 317 (M
++ 1,6), 316 (M
+, 4), 43 (100); HRMS calcd.for C
19H
24O
4
316.1668，
found?316.1651.
Embodiment 8
Reactions steps is with embodiment 2, the different halogenide that step 1 added for to the acetoxyl group iodobenzene, product is:
4-(4 '-acetyloxy phenyl)-5-(normal-butyl)-2 (5 hydrogen)-furanone: yield 87%, purity 83%, oil.
1H NMR (300MHz, CDCl3) δ 7.48 (d, J=8.0Hz, 2H), 7.19 (d, J=8.0Hz, 2H), 6.25 (s, 1H), 5.47 (d, J=6.5Hz, 1H), 2.29 (s, 3H), 1.91-2.10 (m, 1H), 1.20-1.61 (m, 5H), 0.85-0.92 (m, 3H); MS (m/e) 275 (M
++ 1,7), 274 (M
+, 4), 43 (100); HRMS calcd.for C
16H
18O
4
274.1200，
found?274.1209.
Embodiment 9
Reactions steps is with embodiment 6, the different halogenide that step 1 added for to the acetoxyl group bromobenzene, product is:
4-(4 '-acetyloxy phenyl)-5-(cyclohexyl)-2 (5 hydrogen)-furanone (6cc): yield 84%, and purity 87%, solid.
1H NMR (400MHz, CDCl3) δ 7.39 (d, J=8.5Hz, 2H), 7.15 (d, J=8.5Hz, 2H), 6.16 (d, J=1.2Hz, 1H), 5.30 (brs, 1H), 2.24 (s, 3H), 0.80-1.76 (m, 11H); MS (m/e) 301 (M
++ 1,100); HRMS calcd.forC18H2004 300.1356, found 300.1338.
Embodiment 10
Reactions steps is with embodiment 4, the different halogenide that step 1 added for to the acetoxyl group iodobenzene, product is:
4-(4 '-acetyloxy phenyl)-5-(n-hexyl)-3-methyl-2 (5 hydrogen)-furanone: yield 82%, purity 76%, oil.
1H NMR (400MHz, CDCl3) δ 7.01-7.98 (m), 5.30 (brs), 2.28 (s), 2.05 (s), 1.65-1.89 (m), 1.12-1.41 (m), 0.81 (t, J=6.5Hz); MS (m/e) 317 (M
++ 1,3), 316 (M
+, 2), 43 (100); HRMS calcd.for C
19H
24O
4
316.1668，
found?316.1653.
Embodiment 11
Reactions steps is with embodiment 4, the different halogenide that step 1 added for to the acetyl-o-methyl bromobenzene, product is:
4-(4 '-acetyl-o-methyl benzene)-5-(n-heptyl)-2 (5 hydrogen)-furanone: yield 75%, purity 82%, solid.
1H NMR (300MHz, CDCl3) δ 7.52 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 6.24 (s, 1H), 5.48 (d, J=6.0Hz, 1H), 4.50 (s, 2H), 2.16 (s, 3H), 1.92-2.01 (m, 1H), 1.03-1.60 (m, 11H), 0.85 (t, J=6.5Hz, 3H); MS (m/e) 331 (M
++ 1,7), 115 (100); HRMS calcd.for C
20H
26O
4
330.1824，
found330.1850.
Claims (8)
1, the γ-butenolide of aryl substituent is contained in a kind of β position, it is characterized in that molecule is logical
Formula is
R wherein
1, R
2,=H, alkyl, wherein alkyl is C
nH
2n+1, n=1-7; R
3, R
4=H, alkyl, ester group, carboxyl, acetyl-o-methyl, wherein alkyl is C
nH
2n+1, n=1-7.
2, the solid phase synthesis process of the γ-butenolide of aryl substituent is contained in a kind of synthetic β position, it is characterized in that in organic solvent, contain 2 of corresponding group, 3-joins olefin(e) acid, with contain the halid resin of corresponding aryl substituent, under the catalysis of alkali and palladium catalyst, under 60-80 ℃ of condition, react, obtain γ-butenolide that aryl substituent is contained in corresponding resin-carried β position; In the presence of Lewis acid,, obtain γ-butenolide that aryl substituent is contained in the β position again by the organic solvent wash-out; Reaction formula is:
Wherein X=Br, I; R
1, R
2,=H, alkyl, wherein alkyl is C
nH
2n+1, n=1-7;
R
3, R
4=H, alkyl, ester group, carboxyl, acetyl-o-methyl, wherein alkyl is C
nH
2n+1, n=1-7.
3, solid phase synthesis process as claimed in claim 2 is characterized in that used resin is Merrifield resin, Wary resin, Rink resin.
4, solid phase synthesis process as claimed in claim 2 is characterized in that temperature of reaction is 70 ℃.
5, solid phase synthesis process as claimed in claim 2 is characterized in that alkali is salt of wormwood/sodium/caesium, potassium tert.-butoxide/sodium, diisopropyl ethyl amine, triethylamine; 2,3-connection olefin(e) acid is the 2-6 equivalent; Alkali wherein: 2,3-joins olefin(e) acid=2-4: 1.
6, solid phase synthesis process as claimed in claim 2 is characterized in that organic solvent comprises CH
3CN, THF, DMF, DMA, toluene.
7, solid phase synthesis process as claimed in claim 2 is characterized in that palladium catalyst is a tetrakis triphenylphosphine palladium, Pd
2(dba)
3CHCl
3/ PPh
3, Pd (OAc)
2/ PPh
3, PdCl
2/ PPh
3The palladium catalyst consumption is 10%-30%; Wherein 2,3-joins olefin(e) acid: the aryl halide of polymer-supported: palladium catalyst=4: 1: 0.1.
8, solid phase synthesis process as claimed in claim 2 is characterized in that Lewis acid comprises FeCl
3, ZnCl
2, AlCl
3, ZnBr
2, SnCl
4, TiCl
4, ZrCl
4, its consumption is the 3-10 equivalent.
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|---|---|---|---|
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|---|---|---|---|
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| CN115872955A (en) * | 2022-11-30 | 2023-03-31 | 常州兰陵制药有限公司 | Synthesis method of ranitidine intermediate |
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|---|---|---|---|---|
| US5585504A (en) * | 1994-09-16 | 1996-12-17 | Merck & Co., Inc. | Process of making cox-2 inhibitors having a lactone bridge |
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| CN115872955A (en) * | 2022-11-30 | 2023-03-31 | 常州兰陵制药有限公司 | Synthesis method of ranitidine intermediate |
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