CN1106393C - Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process - Google Patents
Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process Download PDFInfo
- Publication number
- CN1106393C CN1106393C CN00127945A CN00127945A CN1106393C CN 1106393 C CN1106393 C CN 1106393C CN 00127945 A CN00127945 A CN 00127945A CN 00127945 A CN00127945 A CN 00127945A CN 1106393 C CN1106393 C CN 1106393C
- Authority
- CN
- China
- Prior art keywords
- optically active
- synthetic method
- organic bases
- active beta
- furanones
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to beta-aryl substitution-2(5H)-furanone with optical activity and a synthetic method thereof, namely that in non-polar solvent, the beta-aryl substitution-2(5H)-furanone is prepared from 1.2 to 6% of aryl iodide and 1% of salt prepared from 2, 3-diolefine acid and chiral organic alkali by reaction at 0 to 25 DEG C under the catalysis of 0.05 to 0.10% of Pd(0) catalyst in the charge ratio. The yield of corresponding beta-aryl substitution-2(5H)-furanone synthesized by the method is from 55 to 90%, and an ee value can reach 91 to 97%. The method has the advantages of mild reaction condition, high yield, single product and easy separation and purification.
Description
The present invention relates to the five-membered ring unsaturated lactone compound that a kind of β position is replaced by aryl, have promptly that optically active beta-aromatic replaces-2 (5H)-furanones and under Pd (O) catalysis aryl iodide and 2, the method for synthesizing this compounds of the reactant salt that 3-di-olefin(e) acid and chirality organic bases generate.
The five-membered ring unsaturated lactone is one of modal structure component in the natural product, has multiple important physical activity.Its antisepsis and anti-inflammation, antimycotic, antitumor, and regulate effects such as seed germination and plant-growth and gained public acceptance, at aspects such as medicine and agricultural chemicals huge value of exploiting and utilizing is arranged.The efficient succinct synthetic of this compounds is the focus of people's common concern always.2 (5H)-Furanones compounds that optically active polyaryl/alkyl replaces may have the more strong physiologically active that racemic this compounds does not have on the one hand, also can overcome on the other hand because a lot of side effects that another optical isomer brought.Two enantiomorphous optical isomers of existing report not only may reduce the performance of medicine on the document, more have some harmful side effects, as the fetus teratogenesis etc.Therefore, synthetic to the chirality of compound with chiral centre, be the particularly problem paid close attention to of Pharmaceutical Chemist of chemist.J.Am.Chem.Sioc.1989 for example, 111,2204; J.Org.Chem.1988, the synthetic of 2 (5H)-Furanones compounds that disclosed optically active polyaryl in 53,4393/alkyl replaces is to prepare from the chiral substrates that is difficult to obtain.Therefore synthetic high biological activity has 2 (5H)-Furanones compounds that optically active polyaryl/alkyl replaces, seeks and prepare this compounds from the chiral source that simply is easy to get, a cheapness, efficient and practical method are provided, still all have positive meaning from experimental implementation safety from the angle of economy.
The object of the invention just provides a kind of optically active beta-aromatic and replaces-2 (5H)-furan ketone compounds, and its molecular formula is:
Wherein: R
1=H, Ph; R
2=Ph, p-BrPh, C
nH
2n+1, n=0-7; R
3=Ar; R
4=C
mH
2m+1, m=0-5.
Another object of the present invention just provides the correlation method of synthetic this compounds, promptly under Pd (O) catalysis, and aryl iodide ArI and 2, the salt of 3-di-olefin(e) acid and the generation of chirality organic bases
Reaction obtains optically active beta-aromatic and replaces-2 (5H)-furanones, and reaction formula is as follows:
Concrete reaction conditions is: in non-polar solvent, and under certain temperature condition, aryl iodide and 2, the salt that 3-di-olefin(e) acid and chirality organic bases generate is through catalyzed reaction 24-72 hour gained of Pd (O).Wherein non-polar solvent is toluene, benzene, dimethylbenzene, normal hexane, hexanaphthene etc.; Temperature of reaction is 0-25 ℃, is recommended as 0-5 ℃; Pd (O) catalyzer is Pd
2(dba)
3CHCl
3(dba is trans 1,5-phenyl-1, and 4-pentadiene-3-ketone, structural formula is
, Pd (PPh
3)
4, allyl palladium chloride, consumption are 5-10mol%; The chirality organic bases is the chirality organic bases of synthetic such as natural organic bases such as cinchovatin, cinchonine and D/L-Alpha-Methyl benzylamine; 2, the feed ratio of the salt that 3-connection olefin(e) acid and chirality organic bases generate, aryl iodide, Pd (O) catalyzer is 1: 1.2-6: 0.05-0.10.
Synthesis of optically active beta-aromatic provided by the invention replaces the method for-2 (5H)-furanones, compared with prior art have following characteristics: reaction uses generate polysubstituted 2 (the 5H)-furanones of high optical activity one step of chiral source that cheaply is easy to get, and the chirality organic bases of use can be recycled; The reaction conditions gentleness, yield is higher, and product is single, is easy to separation and purification; Conversion unit is simple, and cost is low, is easy to industrialization.For the height of realizing this compounds has improved one efficiently, simple approach to selectivity is synthetic.
Following examples help to understand the present invention, but are not limited to content of the present invention.
Embodiment 1
0.1mmol, the 4-phenyl-2-methyl-2 of L-(-)-cinchovatin of 97%ee, 3-divinyl hydrochlorate, 0.12mmol iodobenzene are dissolved in the 3ml toluene, are cooled to-78 ℃, add 5mol%Pd then rapidly
2(dba)
3CHCl
3With the 20mol% triphenylphosphine, be warming up to 0 ℃, stirred 2 days, reaction mixture is directly purified through column chromatography, get pale yellow oily liquid body 22.5mg, yield is 90%, product is (+)-4,5-phenylbenzene-3-methyl-2 (5H)-furanone, data are as follows:
The ee value is 91%;
1H NMR (300MHz, CDCl
3) δ ppm, 7.12-7.38 (m, 10H), 6.19 (s, 1H), 2.17 (s, 3H); Ms (EI, M/e): 250 (M
+, 42.33), 145 (100); IR (pure) 1746,1648,1010cm
-1
Embodiment 2
Reactions steps and reaction conditions are with embodiment 1, and reactant is 0.1mmol, the 4-phenyl-2-methyl-2 of 97%ee L-(-)-Alpha-Methyl benzylamine, and 3-divinyl hydrochlorate and 0.3mmol iodobenzene are dissolved in the 4ml dimethylbenzene, add the Pd (PPh of 8mol%
3)
4, stirring 36 hours, its yield is 85%, product is with embodiment 1,
The ee value is 93%;
Other data are with embodiment 1.
Embodiment 3
Reactions steps and reaction conditions are with embodiment 1, reactant is 0.1mmol, 4-phenyl-2-the methyl-2 of the D-(+) of 98%ee-Alpha-Methyl benzylamine, 3-divinyl hydrochlorate and 0.24mmol iodobenzene are dissolved in the 3ml hexanaphthene, add the 10mmol% allyl palladium chloride, be warming up to 10 ℃ and stirred 24 hours down, get the pale yellow oily liquid body, productive rate is 66%, product is (-)-4,5-phenylbenzene-3-methyl-2 (5H)-furanone.
The ee value is 96%;
1H?NMR(300MHz，CDCl
3)δppm，7.08-7.40(m，10H)，6.19(s，1H)，2.14(s，3H)。
Embodiment 4
With 0.01mmol, 4-phenyl-2-the methyl-2 of L-(-)-cinchovatin of 97% ee, 4-phenyl-2-the methyl-2 of the L-(-) of 3-divinyl hydrochlorate or 97% ee-Alpha-Methyl benzylamine, 3-divinyl hydrochlorate and 0.02mmol are dissolved in the 4ml benzene toluene iodide, be cooled to-78 ℃, add 5mol%Pd then rapidly
2(dba)
3CHCl
3With the 20mol% triphenylphosphine, be warming up to 5 ℃, stirred 24 hours, obtain weak yellow liquid, productive rate and ee% are respectively 66%, 92% ee or 65%, 91%ee.The data of (+)-3-methyl-4-(4 '-aminomethyl phenyl)-5-phenyl-2 (5H)-furanone are as follows:
1H?NMR(300MHz，CDCl
3)δppm，7.03-7.18(m，9H)，6.06(s，1H)，2.20(s，3H)，2.02(d，J＝1.4Hz，3H)；
Ms(EI，M/e)264(M
+，44.76)，159(100)；
IR (pure) 1746,1650,1610,1092,1030cm
-1
HRMS?C
18H
16O
2：
Calculated value: 264.1146, measured value: 264.11403.
Embodiment 5
Reactions steps and reaction conditions are with embodiment 4, reactant is 0.1mmol, 4-phenyl-2-the methyl-2 of the D-(+) of 98% ee-Alpha-Methyl benzylamine, 3-divinyl hydrochlorate and 0.4mmol are to toluene iodide, productive rate is 72%, the pale yellow oily liquid body, the data of product (-)-3-methyl-4-(4 '-aminomethyl phenyl)-5-phenyl-2 (5H)-furanone are as follows:
Ee value: 97%;
1H?NMR(300MHz，CDCl
3)δppm，7.03-7.18(m，9H)，6.06(s，1H)，2.20(s，3H)，2.02(d，J＝1.4Hz，3H)；
Ms(EI，M/e)264(M
+，44.76)，159(100)；IR(neat)1746，1650，1610，1092，1030cm
-1。
Embodiment 6
Reactions steps and reaction conditions are with embodiment 2, reactant is 0.1mmol, 4-phenyl-2-n-propyl-2 of 98%ee, 3-divinyl acid L-(-)-cinchovatin connection olefin(e) acid salt and 0.5mmol iodobenzene, product is a weak yellow liquid, productive rate is 72%, and product is (+)-4,5-phenylbenzene-3-n-propyl-2 (5H)-furanone.Data are as follows:
Ee value: 91%;
1H?NMR(300MHz，CDCl
3)δppm，7.11-7.39(m，10H)，6.13(s，1H)，2.45-2.56(m，2H)，1.64-1.80(m，2H)，1.00(t，J＝7.5Hz)；
Ms(EI，m/e)278(M+，71.55)，173(100)，115(99.13)；
IR (pure) 1746,1648,1098,1010cm
-1
HRMS?C
19H
18O
2：
Calculated value: 278.1302, measured value: 278.12916.
Embodiment 7
Reactions steps and reaction conditions are with embodiment 3, reactant is 0.1mmol, the L-(-) of 98% ee-cinchovatin 4-phenyl-2-n-propyl-2,3-divinyl hydrochlorate and 0.12mmol are to toluene iodide, product is a weak yellow liquid, productive rate is 75%, and product (+)-3-n-propyl-(4 '-aminomethyl phenyl)-5-phenyl-2 (5H)-furanone data are as follows:
Ee value: 91%;
1H?NMR(300?MHz，CDCl
3)δ?ppm，7.08-7.30(m，9H)，6.12(s，1H)，2.45-2.53(m，2H)，2.29(s，3H)，1.60-1.74(m，2H)，0.98(t，J＝7.4Hz)；
Ms(EI，M/e)292(M
+，70.80)，187(100)；
IR (pure) 1746,1648,1098,1010cm
-1
HRMS?C
20H
20O
2：
Calculated value: 292.1458, measured value: 292.1449.
Embodiment 8
Reactions steps and reaction conditions embodiment 4, reactant are 0.1mmol, the L-(-) of 97% ee-cinchovatin 2, the iodobenzene of 3-diene ten-hydrochlorate and 0.3mmol is dissolved in the 5ml hexanaphthene, add allyl palladium chloride 10mmol%, reaction obtains weak yellow liquid under the room temperature, and productive rate is 75%; The data of product (+)-4-phenyl-5-n-heptyl-2 (5H)-furanone are as follows:
Ee value: 94%;
1H?NMR(300MHz，CDCl
3)δppm，7.44-7.53(m，5H)，6.28(s，1H)，5.42-5.50(m，1H)，1.92-2.03(m，1H)，1.49-1.60(m，1H)，1.11-1.48(m，10H)，0.85(t，J＝6.7Hz)。
Embodiment 9
With 0.01mmol, the 4-phenyl-2-methyl-2 of the D-(+) of 98%ee-Alpha-Methyl benzylamine in 3-divinyl hydrochlorate and the 0.06mmol 4-Iodobenzoic acid methyl esters dissolving 5ml normal hexane, adds 5mol%Pd
2(dba)
3CHCl
3With the 20mol% triphenylphosphine, be warming up to 15 ℃, stirred 30 hours, productive rate is 58%. white solids, the data of product (-)-3-methyl-4-(4 '-methoxycarbonyl phenyl)-5-phenyl-2 (5H)-furanone are as follows:
The ee value is 94%;
mp：43.5-45℃；
1H?NMR(300MHz，CDCl
3)δppm?7.92(d，J＝8.3Hz，2H)，7.03-7.22(m，7H)，6.06(s，1H)，3.78(s，3H)，2.04(s，3H)；
Ms(EI，M/e)308(M+，69.26)，203(100)；
IR(KBr)1748，1746，1608，1028cm
-1；
HRMS?C
19H
16O
4：
Calculated value: 308.1044, measured value: 308.10438.
Claims (6)
1, a kind of have optically active beta-aromatic and replace-2 (5H)-furanones, it is characterized in that the compound molecule general formula is:
Wherein: R
1=H, Ph; R
2=Ph, p-BrPh, C
nH
2n+1, n=0-7; R
3=Ar; R
4=C
mH
2m+1, m=0-5.
2, a kind of synthetic method that optically active beta-aromatic replaces-2 (5H)-furanones that has, it is characterized in that in non-polar solvent, under 0-25 ℃ temperature condition, aryl iodide and 2, the salt that 3-di-olefin(e) acid and chirality organic bases generate is under the catalysis of Pd (O) catalyzer, reaction obtains optically active beta-aromatic and replaces-2 (5H)-furanones, and its reaction formula is as follows:
Wherein: R
1=H, Ph; R
2=Ph, p-BrPh, C
nH
2n+1, n=0-7; R
4=C
mH
2m+1, m=0-5; B is the chirality organic bases; 2, the feed ratio of the salt that 3-connection olefin(e) acid and chirality organic bases generate, aryl iodide, Pd (O) catalyzer is 1: 1.2-6: 0.05-0.10.
3, synthetic method as claimed in claim 1 or 2 is characterized in that non-polar solvent is toluene, benzene, dimethylbenzene, normal hexane, hexanaphthene.
4, synthetic method as claimed in claim 1 or 2 is characterized in that the chirality organic bases is cinchovatin, cinchonine and D/L-Alpha-Methyl benzylamine.
5, synthetic method as claimed in claim 1 or 2 is characterized in that Pd (O) catalyzer is Pd
2(dba)
3CHCl
3, Pd (PPh
3)
4, allyl palladium chloride, consumption is 5-10mol%.
6, synthetic method as claimed in claim 1 or 2 is characterized in that temperature of reaction is 0-5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00127945A CN1106393C (en) | 2000-12-19 | 2000-12-19 | Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00127945A CN1106393C (en) | 2000-12-19 | 2000-12-19 | Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1299816A CN1299816A (en) | 2001-06-20 |
| CN1106393C true CN1106393C (en) | 2003-04-23 |
Family
ID=4592855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00127945A Expired - Fee Related CN1106393C (en) | 2000-12-19 | 2000-12-19 | Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1106393C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103274A (en) * | 1986-05-05 | 1988-01-20 | 威廉施瓦布博士有限公司 | 5-aralkyl-4-alkoxyl group-2 (5H)-furanone, intermediate product and preparation method thereof and as the use of medicine |
-
2000
- 2000-12-19 CN CN00127945A patent/CN1106393C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103274A (en) * | 1986-05-05 | 1988-01-20 | 威廉施瓦布博士有限公司 | 5-aralkyl-4-alkoxyl group-2 (5H)-furanone, intermediate product and preparation method thereof and as the use of medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1299816A (en) | 2001-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1821242A (en) | Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor | |
| CN1366526A (en) | Process for preparation of pure citalopram | |
| CN1705664A (en) | Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine | |
| CN1290818C (en) | Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol | |
| CN1121381C (en) | Novel process for preparing ketimine | |
| CN1063422C (en) | Production of optically active 2-halo-1-(substituted phenyl) ethanol and substituted styrene oxide | |
| CN1276911C (en) | New phenyl ethyl amine compounds having beta 2-receptor excitation and its producing method | |
| CN1025328C (en) | Process for preparing sertraline intermediates | |
| CN1106393C (en) | Optically active beta-aryl substitution-2(5H)-ketofuran and its synthesis process | |
| CN1268889A (en) | Novel process for obtg. intermediates | |
| CN1765892A (en) | Orlistat preparation method | |
| CN102286036A (en) | Synthesis method of rhodioside | |
| CN1161353C (en) | Process for production of paroxetine | |
| CN1182113C (en) | 2,5-cis-bisubstituted pyrrolidine derivative and its preparing process and usage | |
| CN1675200A (en) | Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy -6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide | |
| CN1266155C (en) | 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2,3-e)-1,2-thiazine-1,1-dioxide-3 | |
| CN101709313B (en) | Method for catalytic synthesizing beta-nitroalcohol compounds by using lipase in organic phase | |
| CN1102587C (en) | Optically active beta-halo-gamma-crotonic lactone and its synthesis process | |
| CN1176924C (en) | Chirality catalyst for oxidative coupling naphthol | |
| CN1062552C (en) | Cyclohexadiene derivatives | |
| CN1727329A (en) | New method for synthesizing Gabapentin hydrochloride | |
| CN1348437A (en) | A method of preparing cyclohexanecaraboxylic acid using [2+4] Diels-Alder reaction | |
| CN1102586C (en) | Gamma-butenolide containing aryl substituent at beta position and its solid-phase synthesis process | |
| CN1955185A (en) | Optical active substitution oxyphosphonate salt acetate and its use | |
| CN1189458C (en) | Method for producing high purity antimer of (2s,3s)-1-tert-butoxy carbonyl-3-hydroxy-2-phenyl piperidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20030423 Termination date: 20151219 |
|
| EXPY | Termination of patent right or utility model |