CN101560184A - N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof - Google Patents
N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof Download PDFInfo
- Publication number
- CN101560184A CN101560184A CNA2008100442213A CN200810044221A CN101560184A CN 101560184 A CN101560184 A CN 101560184A CN A2008100442213 A CNA2008100442213 A CN A2008100442213A CN 200810044221 A CN200810044221 A CN 200810044221A CN 101560184 A CN101560184 A CN 101560184A
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydrogen
- quaternary ammonium
- ammonium salt
- benzyl
- 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.)
- Pending
Links
Abstract
The invention belongs to the field of the organic chemistry, in particular to an N-chiral quaternary ammonium salt derived from amino acid and a preparation method thereof. The N-chiral quaternary ammonium salt derived from the amino acid has the structural characteristic as right, wherein R1 is a hydrogen or a methyl; R2 is the hydrogen or the methyl; R3 is the hydrogen, the methyl or an oxygroup; R4 is the hydrogen, the methyl or the oxygroup; R5 is the hydrogen, the methyl or the oxygroup; and R6 is a 3-isobutyl, a phenmethyl or a phenethyl. The preparation method comprises the synthesis and the splitting of the quaternary ammonium salt, wherein the splitting method respectively comprises an inclusion splitting method and an acetone precipitation splitting method.
Description
Technical field
The invention belongs to organic chemistry filed, be specifically related to N-chiral quaternary ammonium salt of several derived from amino acid and preparation method thereof.
Background technology
The phase-transfer catalyst that grow up the seventies in last century is widely used in organic synthesis.The design of chiral quaternary ammonium salt phase-transfer catalyst and the application in asymmetric synthesis thereof have caused concern (a.Org.Lett., 2000, the 2:2959 of more and more chemists as a newer problem; B.Tetrahedron Lett., 1998,39:1599.).Research chiral quaternary ammonium salt more, good catalytic activity is mainly cinchona alkaloid analog derivative (a.Tetrahedron, 1999,55:6289 at present; B.Tetrahedron Lett., 1998,39:7563; C.Tetrahedron:Asymmetry, 2001,12:121; D.Tetrahedron Lett., 1998,39:2145; E.Tetrahedron Lett., 1998,39:8299; F.Tetrahedron Lett., 1999,40:3843; G.J.Am.Chem.Soc.1997,119,12414.) and a class of design such as Maruoka have C
2Volution chiral quaternary ammonium salt (a.J.Am.Chem.Soc., 2003, the 125:2054 of symmetry axis; B.Tetrahedron Lett., 1996,37:3183; C.Tetrahedron Lett., 1998,39:2997; D.J.Org.Chem., 2004,69:2874,11:1123; E.Angew.Chem.Int.Ed.2003,42,3796; F.Organic Lett.2001,3,1273.).They all possess characteristics such as rigid structure, conformation are fixed, the quaternary ammonium salinization is simple.But because this compounds kind is limited, the structure of modification difficulty has brought limitation for the structure choice and the Application Expansion of catalyzer.Therefore seek the source of other chiral quaternary ammonium salt, the type of research asymmetric catalysis deeply is familiar with asymmetry catalysis mechanism, is a significant job.
Cinchona alkaloid deutero-quaternary ammonium salt
Chiral binaphthol deutero-quaternary ammonium salt
Amino acid is the chiral source that cheaply is easy to get that occurring in nature extensively exists, and in addition, amino acid itself possesses rich functions group (as big π key, carboxyl, hydroxyl etc.), is easy to carry out structure of modification.Synthetic and Catalytic Performance to the amino acid quaternary ammonium salt focuses mostly on the proline(Pro) analog derivative at present.1998, Dehmlow (Tetrahedron:Asymmetry, 1998,9:2235) group's report is a raw material with proline(Pro), some new chiral quaternary ammonium salt type phase-transfer catalysts have been synthesized, its chiral centre comprises N and C, has measured their catalytic activitys in reactions such as substitution reaction, reduction reaction, Gabriel reaction, Michael reaction then, and the result shows that these selectivity of catalyst can not show a candle to the quaternary ammonium salt of cinchona alkaloid class.N-chiral centre quaternary ammonium salt study fewerly.The quaternary ammonium salt of chirality nitrogen-atoms on ring generally splits (a.Tetrahedron:Asymmetry, 1998,9:2235 by forming the diastereomer recrystallization; B.Org.Lett., 1999,1,31; C.Heterocycles, 2005,66,95; D.Chemistry Letters, 2006,35,478.).Reported that at Eiji Tayama in 2007 the quaternary ammonium salt formation inclusion mixture with chiral binaphthol and part beta-hydroxy tetraalkyl N-chiral centre splits (Tetrahedron Letters, 2007,48,4183.).With chiral quaternary ammonium salt the compound of dinaphthol and similar thereof is split the aspect simultaneously report (a.J.Org.Chem., 1994,59,5748 are also arranged; B.Tetrahedron, 2000,56,4447; C.Org.Biomol.Chem., 2004,2,449; D.Tetrahedron:Asymmetry, 2006,17,854.).Up to the present, to chiral amino acid deutero-N-chiral quaternary ammonium salt method for splitting research nobody's report also of the amino acid derived N-chiral quaternary ammonium salt of chirality chain particularly.
Eiji Tayama forms the inclusion mixture with chiral binaphthol and quaternary ammonium salt and splits N-chiral centre quaternary ammonium salt
Dehmlow group is the part chiral quaternary ammonium salt that raw material is synthetic and split with proline(Pro)
Summary of the invention
The purpose of this invention is to provide several new texture chiral quaternary ammonium salts, its structural formula is as follows:
Wherein: R
1=hydrogen or methyl; R
2=hydrogen or methyl; R
3=hydrogen, methyl or methoxy; R
4=hydrogen, methyl or methoxy; R
5=hydrogen, methyl or methoxy; R
6=3-isobutyl-, benzyl or styroyl.
The method for preparing these several new texture chiral quaternary ammonium salts is as follows respectively:
One, quaternary ammonium salt is synthetic
As follows from the synthetic route of the intermediate material of alanine methyl ester hydrochloride synthetic compound 1 and 2:
R
1=hydrogen or methyl; R
2=hydrogen or methyl.
From S-1,2,3, the synthetic route of the intermediate material of 4-tetrahydroisoquinoline-3-carboxylic acid synthetic compound 3 is as follows:
As follows from the synthetic route of the intermediate material of amino acid methyl ester hydrochloride synthetic compound 4 and 5:
R1=hydrogen or methyl; R2=hydrogen or methyl; R3=hydrogen, methyl or methoxy; R4=hydrogen, methyl or methoxy; R5=hydrogen, methyl or methoxy; R6=3-isobutyl-, benzyl or styroyl.
Two, the fractionation of quaternary ammonium salt
Split above-mentioned quaternary ammonium salt diastereomer with inclusion Split Method and acetone precipitation respectively, obtain corresponding chiral quaternary ammonium salt.
Work as R
6When=3-isobutyl-or benzyl:
Work as R
6During=styroyl:
Characteristics of the present invention are: method is simple, and cost is low, and the productive rate height is easily realized industrialization.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but do not limit content of the present invention.
Embodiment 1: from L-alanine methyl ester hydrochloride synthetic and split and obtain (2S, NS)-N-methyl-N-allyl group-N-benzyl-(1-hydroxypropyl)-2-brometo de amonio and (2S, NR)-N-methyl-N-allyl group-N-benzyl-(1-hydroxypropyl)-2-brometo de amonio:
L-alanine methyl ester hydrochloride (1a) is to N-methyl-N-benzyl-L-alanine methyl ester (1b) (method for the treatment of different things alike):
Add anhydrous Na HCO31.26g under condition of ice bath, stir 1h in the 60ml absolute methanol solution that is dissolved with 1a 1.40g (10mmol), the pH value that makes reaction system is 7.0～8.0.(1.06g 10mmol), at room temperature stirs 5h then to add phenyl aldehyde 1.02ml in reaction system.Then the condition downhill reaction system at ice bath slowly adds 0.27g (5mmol) KBH4, behind the reaction 1h, adds 37% formaldehyde solution 1.47ml (20mmol) in reaction system, reacts 6h at normal temperatures.Then under the condition of ice bath, in reaction system, add KBH4 1.08g (20mmol), reaction 10h.The evaporate to dryness reaction system with the ethyl acetate extraction of 3 * 20ml, anhydrous Na 2SO4 drying, is filtered, and evaporated under reduced pressure obtains faint yellow oily thing, and silica gel column chromatography (petroleum ether-ethyl acetate, 15: 1) obtains compound 1b 1.90g (9.1mmol, yield are 91%).
N-methyl-N-benzyl-L-alanine methyl ester (1b) is reduced into N-methyl-N-benzyl-L-Propanolamine (1c):
The LiAlH4 that under condition of ice bath, in the 60ml anhydrous ether solution that is dissolved with 1b 1.90g (9.1mmol), slowly adds 0.173g (4.5mmol), stir 2h, then add ether 40ml in condition of ice bath, the water that slowly adds 0.2ml then, the saturated NaOH solution that then adds 0.2ml, add 0.6ml water at last, stir, reaction system becomes the white casse thing.2h after-filtration reaction system, and wash precipitation 3 times with ethyl acetate, washings is incorporated filtrate into, and filtrate is filtered with anhydrous Na 2SO4 drying, and evaporated under reduced pressure obtains lark oily matter 1c 1.60g (8.9mmol, yield are 98%).
N-methyl-N-benzyl-L-Propanolamine quaternized (1c) obtains [2S, NS (R)]-N-methyl-N-allyl group-N-benzyl-(1-hydroxypropyl)-2-brometo de amonio:
The allyl bromide 98 that in the round-bottomed flask that compound 1c 1.60g (8.9mmol) is housed, adds 10ml anhydrous acetonitrile and 1.6ml (17.8mmol), stirring reaction 8h under the condition that refluxes.Follow evaporate to dryness reaction solvent and allyl bromide 98, silica gel column chromatography separates, and collects product, obtains 1d 2.19g (7.31mmol, yield are 85%).
Split process:
The S-BINOL (S-dinaphthol) that adds 172mg (0.603mmol) in the dichloromethane solution of the 4ml that is dissolved with 1d 411mg (1.37mmol) at room temperature stirs, and white precipitate occurs.The 24h after-filtration, precipitation must precipitate 339mg (yield is 96%) with a small amount of methylene dichloride (1ml) washing.The precipitation recrystallizing methanol, obtain white solid 300mg (yield is 88.5%), white solid water-extracted with diethyl ether is collected and the evaporate to dryness water, obtain compound 2 (2S, NR)-N-methyl-N-allyl group-N-benzyl-(1-hydroxypropyl)-2-brometo de amonio 149mg (yield is 97%).Evaporated under reduced pressure 5ml filtrate, water-extracted with diethyl ether again, collect and the evaporate to dryness water, then to the methylene dichloride that wherein adds 3ml, at room temperature stir 24h then, the white depositions that produces is filtered, precipitation is washed with a small amount of methylene dichloride (1ml), obtain white solid 368mg (yield is 93%), precipitation is used recrystallizing methanol, obtains white solid 302mg (yield is 82%), white solid is water-extracted with diethyl ether again, the evaporate to dryness water, obtain compound 1 (2S, NS)-N-methyl-N-allyl group-N-benzyl-(1-hydroxypropyl)-2-brometo de amonio 148mg (yield is 97%).
Embodiment 2: the synthetic and fractionation of compound 3:
From S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2a) synthesizes the S-2-methyl isophthalic acid, and 2,3,4-tetrahydrochysene-3-isoquinoline 99.9 methyl alcohol (2c):
Vinyl chloroformate (the 1.14g that under condition of ice bath, adds NaHCO3 1.68g (20mmol) and 1ml successively to the THF of the 20ml that is dissolved with 2a 1.77g (10mmol) and the mixing solutions of water (volume ratio of THF and water is 1: 1), 10.5mmol), then allow the temperature of reaction system slowly rise to room temperature, stir 3h after being raised to room temperature by 0 ℃.Reaction system is diluted with 10ml water then, regulate pH to 8-10 with 10% sodium hydroxide solution again, then with ethyl acetate extraction (15ml * 2), water is used ethyl acetate extraction (15ml * 3) after with 10% hcl acidifying again, merges organic phase twice, with twice of saturated common salt washing, anhydrous Na SO4 drying is filtered the evaporated under reduced pressure organic solvent, obtain the solid 2b 2.465g (9.9mmol) of white, yield is 99%.
The 2b that in the anhydrous THF of the 25ml of the lithium aluminum hydride that is dissolved with 0.95g (25mmol), adds 1.245g (5mmol), reaction system refluxes and stirs 5h, then under condition of ice bath, slowly drip the water of 0.88ml successively to reaction system, 0.88ml 10%NaOH solution, 0.88ml water, then stir 2h.Then add anhydrous Na SO4 in reaction system, filter, obtain the liquid of lark, evaporated under reduced pressure with methylene dichloride/hexanaphthene recrystallization, obtains clear crystal 2c 0.68g (3.85mmol), and yield is 77%.
The S-2-methyl isophthalic acid, 2,3, the 4-tetrahydrochysene-quaternized 2d that obtains of 3-isoquinoline 99.9 methyl alcohol (2c):
The allyl bromide 98 that in the round-bottomed flask that compound 2c 1.58g (8.9mmol) is housed, adds 10ml anhydrous acetonitrile and 1.6ml (17.8mmol), stirring reaction 3h under the condition that refluxes.The evaporate to dryness reaction solvent, silica gel column chromatography (ethyl ester ethyl ester: methyl alcohol 20: 1), collect product, obtain 2d 2.39g (8.0mmol, yield are 90%).
Split quaternary ammonium salt 2d:
The S-BINOL (S-dinaphthol) that adds 286mg (1mmol) in the dichloromethane solution of the 5ml that is dissolved with 2d 596mg (2mmol) at room temperature stirs, and the dregs of white occurs.The 24h after-filtration, precipitation must precipitate 385mg (yield is 66%) with a small amount of methylene dichloride (1ml) washing.Then water-extracted with diethyl ether, the evaporate to dryness water, obtain R-2d (3S, NR)-N-methyl-N-allyl group-3-methylol-(1,2,3, the 4-tetrahydro isoquinolyl)-2-brometo de amonio 190mg (yield is 97%).
The S-2-methyl isophthalic acid, 2,3, the 4-tetrahydrochysene-quaternized 2e that obtains of 3-isoquinoline 99.9 methyl alcohol (2c):
The isopentene group bromine that in the round-bottomed flask that compound 2c 1.58g (8.9mmol) is housed, adds 10ml anhydrous acetonitrile and 2.1ml (17.8mmol), stirring reaction 4h under the condition that acetonitrile refluxes.Follow the evaporate to dryness reaction solvent, silica gel column chromatography (ethyl ester ethyl ester: methyl alcohol 20: 1), collect product, obtain 2e 2.63g (8.1mmol, yield are 91%).
Split quaternary ammonium salt 2e:
The S-BINOL that adds 429mg (1.5mmol) in the dichloromethane solution of the 10ml that is dissolved with 2e 978mg (3mmol) at room temperature stirs, and the dregs of white occurs.The 24h after-filtration, precipitation must precipitate 523mg (yield is 57%) with a small amount of methylene dichloride (2ml) washing.Then water-extracted with diethyl ether, the evaporate to dryness water, obtain compound 3 (3S, NR)-N-methyl-N-isopropyl pentenyl-3-methylol-(1,2,3, the 4-tetrahydro isoquinolyl)-2-brometo de amonio 269mg (yield is 97%).
Embodiment 3: from L-phenylalanine methyl ester hydrochloride (4a) synthetic and split and obtain (2S, NS)-N-methyl-N-allyl group-N-benzyl-(3-phenyl-1-hydroxypropyl)-2-brometo de amonio (4):
From L-phenylalanine methyl ester hydrochloride (4a) to the N-methyl-N-benzyl-L-phenylalanine methyl ester (4b) (method for the treatment of different things alike):
Under condition of ice bath, in the 50ml absolute methanol solution that is dissolved with 4a 2.15g (10mmol), add anhydrous Na HCO
31.26g, stirring 1h, the pH value that makes reaction system is 7.0～8.0.Then in the reaction system adding phenyl aldehyde 1.02ml (1.06g 10mmol), at room temperature stirs 6h.Then the condition downhill reaction system at ice bath slowly adds 0.27g (5mmol) KBH
4, behind the reaction 1h, in reaction system, add 37% formalin 1.47ml (20mmol), react 6h at normal temperatures.Then under the condition of ice bath, in reaction system, add KBH
41.08g (20mmol), reaction 8h.The evaporate to dryness reaction system is with the ethyl acetate extraction of 3 * 20ml, anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains faint yellow oily thing, and silica gel column chromatography (petroleum ether-ethyl acetate, 20: 1) obtains compound 4b 2.51g (8.9mmol, yield are 89%).
N-methyl-N-benzyl-L-phenylalanine methyl ester (4b) is reduced into N-methyl-N-benzyl-L-phenylalaninol (4c):
The LiAlH that under condition of ice bath, in the 60ml anhydrous ether solution that is dissolved with 4b 2.51g (8.9mmol), slowly adds 0.170g (4.5mmol)
4, stir 2h, in reaction system, add ether 40ml in condition of ice bath, the water that slowly adds 0.2ml then to reaction system, the then slow saturated NaOH solution that adds 0.2ml, the last water that slowly adds 0.6ml again, stir, reaction system produces the white casse thing.Behind the 1h, the filtering reaction system, and use the ethyl acetate washing precipitation, filtrate is used anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains lark oily matter 4c 2.20g (8.6mmol, yield are 97%).
N-methyl-N-benzyl-L-phenylalaninol (4c) quaternized and by the precipitator method obtain (2S, NS)-N-methyl-N-allyl group-N-benzyl-(3-phenyl-1-hydroxypropyl)-2-brometo de amonio (4):
The allyl bromide 98 that in the round-bottomed flask that 4c 2.20g (8.6mmol) is housed, adds 10ml anhydrous acetonitrile and 1.5ml (17.2mmol), stirring reaction 18h under the condition that refluxes.Evaporate to dryness reaction solvent and allyl bromide 98 to the acetone of its adding 10ml, stir again, white precipitate occurs.The 2h after-filtration with small amount of acetone (2ml) washing precipitation, obtains compound 41.02g (yield is 30%).
Embodiment 4: from L-leucine methyl ester hydrochloride synthetic and split and obtain (2S, NS)-N-methyl-N-allyl group-N-benzyl-(4-methyl isophthalic acid-hydroxyl amyl group)-2-brometo de amonio (4):
From L-leucine methyl ester hydrochloride (5a) to the N-methyl-N-benzyl-L-leucine methyl esters (5b):
Under condition of ice bath, in the 100ml absolute methanol solution that is dissolved with 5a 3.64g (20mmol), add anhydrous Na HCO
32.56g, stir 1h, making pH value of reaction system is 7.0～8.0.Then in the reaction system adding phenyl aldehyde 2.04ml (2.12g 20mmol), at room temperature stirs 5h.Then the condition downhill reaction system at ice bath slowly adds 0.54g (10mmol) KBH
4, behind the reaction 1h, in reaction system, add saturated formaldehyde solution 2.84ml (40mmol), react 5h at normal temperatures.Then under the condition of ice bath, in reaction system, add KBH
42.16g (40mmol), reaction 8h.The evaporate to dryness reaction system is with the ethyl acetate extraction of 3 * 50ml, anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains yellow oil, and silica gel column chromatography (petroleum ether-ethyl acetate, 20: 1) obtains compound 5b 4.53g (18.2mmol, yield are 91%).
N-methyl-N-benzyl-L-leucine methyl esters (5b) is reduced into N-methyl-N-benzyl-L-leucinol (5c):
The LiAlH that under condition of ice bath, in the 100ml anhydrous ether solution that is dissolved with 5b 4.53g (18.2mmol), slowly adds 0.346g (9.1mmol)
4, stir 2h, in reaction system, add ether 40ml in condition of ice bath, the water that slowly adds 0.4ml then to reaction system then slowly adds the saturated NaOH solution of 0.4ml again, the last water that slowly adds 1.2ml, stir, reaction system produces the white casse thing.Behind the 1h, the filtering reaction system, and wash precipitation with ethyl acetate, filtrate is used anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains lark oily matter 5c 3.94g (17.8mmol, yield are 98%).
N-methyl-N-benzyl-L-leucinol (5c) quaternized and by the precipitator method obtain (2S, NS)-N-methyl-N-allyl group-N-benzyl-(4-methyl 1-hydroxyl amyl group)-2-brometo de amonio (4):
The allyl bromide 98 that in the round-bottomed flask that 5c 3.94g (17.8mmol) is housed, adds 20ml anhydrous acetonitrile and 3.1ml (35.6mmol), stirring reaction 24h under the condition that refluxes.Evaporate to dryness reaction solvent and allyl bromide 98 again to the acetone that wherein adds 15ml, stir, and white precipitate occurs, and the 2h after-filtration with small amount of acetone (2ml) washing, obtains 41.58g (yield is 26%).
Embodiment 5: synthetic and split and obtain (2S from L-hyperphenylalaninemia methyl ester hydrochloride, NS)-N-methyl-N-allyl group-N-benzyl-(4-phenyl-1-hydroxybutyl)-2-brometo de amonio and (2S, NR)-N-methyl-N-allyl group-N-benzyl-(4-phenyl-1-hydroxybutyl)-2-brometo de amonio:
From L-hyperphenylalaninemia methyl ester hydrochloride (6a) to the N-methyl-N-benzyl-L-hyperphenylalaninemia methyl esters (6b)
Under condition of ice bath, in the 100ml absolute methanol solution that is dissolved with 6a 4.86g (20mmol), add anhydrous Na HCO
32.56g, stir 1h, making its pH value is 7.0～8.0.Then in the reaction system adding phenyl aldehyde 2.04ml (2.12g 20mmol), stirs 7h under the chamber, chamber.Then the condition downhill reaction system at ice bath slowly adds 0.54g (10mmol) KBH
4, behind the reaction 1h, in reaction system, add saturated formaldehyde solution 2.84ml (40mmol), react 6h at normal temperatures.Then under the condition of ice bath, in reaction system, add KBH
42.16g (40mmol), reaction 8h.The evaporate to dryness reaction system is with the ethyl acetate extraction of 3 * 50ml, anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains yellow oil, and silica gel column chromatography (petroleum ether-ethyl acetate, 25: 1) obtains compound 6b 5.60g (18.0mmol, yield are 90%).
N-methyl-N-benzyl-L-hyperphenylalaninemia methyl esters (6b) is reduced into N-methyl-high phenylalaninol of N-benzyl-L-(6c):
The LiAlH that under condition of ice bath, in the 100ml anhydrous ether solution that is dissolved with 6b 5.60g (18.0mmol), slowly adds 0.346g (9.1mmol)
4, stirring reaction 2h.Add ether 40ml in condition of ice bath in reaction system, slowly add the water of 0.4ml then, then slowly add the saturated NaOH solution of 0.4ml, the last water that slowly adds 1.2ml stirs, and reaction system produces the white casse thing.2h after-filtration reaction system, and wash precipitation with ethyl acetate, filtrate is used anhydrous Na
2SO
4Drying is filtered, and evaporated under reduced pressure obtains lark oily matter 6c 4.75g (17.6mmol, yield are 98%).
N-methyl-high phenylalaninol of N-benzyl-L-(6c) is quaternized and obtain (2S by the precipitator method, NS)-N-methyl-N-allyl group-N-benzyl-(4-phenyl-1-hydroxybutyl)-2-brometo de amonio (4) and (2S, NR)-N-methyl-N-allyl group-N-benzyl-(4-phenyl-1-hydroxybutyl)-2-brometo de amonio (5):
The allyl bromide 98 that in the round-bottomed flask that 6c 4.75g (17.6mmol) is housed, adds 20ml anhydrous acetonitrile and 3.1ml (35.6mmol), stirring reaction 24h under the condition that refluxes.Evaporate to dryness reaction solvent and allyl bromide 98 again to the acetone that wherein adds 15ml, stir 5h, white precipitate occurs, filter, and with acetone 5ml washing precipitation (washings is not incorporated in the filtrate), obtain 53.01g (yield is 45%).Evaporated under reduced pressure filtrate, silica gel column chromatography (ethyl acetate: methyl alcohol 50: 1), product and raw material are separated, collect product and obtain flaxen oily matter 3.09g (yield is 41%), be 4.
Claims (2)
1, the N-chiral quaternary ammonium salt of several derived from amino acid has following constitutional features:
Wherein: R1=hydrogen or methyl; R2=hydrogen or methyl; R3=hydrogen, methyl or methoxy; R4=hydrogen, methyl or methoxy; R5=hydrogen, methyl or methoxy; R6=3-isobutyl-, benzyl or styroyl.
2, the preparation method of the described N-chiral quaternary ammonium salt of claim 1 is:
The first step: quaternary ammonium salt synthetic
As follows from the synthetic route of the intermediate material of alanine methyl ester hydrochloride synthetic compound 1 and 2:
R
1=hydrogen or methyl; R
2=hydrogen or methyl.
From S-1,2,3, the synthetic route of the intermediate material of 4-tetrahydroisoquinoline-3-carboxylic acid synthetic compound 3 is as follows:
R1=hydrogen or methyl; R2=hydrogen or methyl.
As follows from the synthetic route of the intermediate material of amino acid methyl ester hydrochloride synthetic compound 4 and 5:
R1=hydrogen or methyl; R2=hydrogen or methyl; R3=hydrogen, methyl or methoxy; R4=hydrogen, methyl or methoxy; R5=hydrogen, methyl or methoxy; R6=3-isobutyl-, benzyl or styroyl;
Second step: the fractionation of quaternary ammonium salt
Split above-mentioned quaternary ammonium salt diastereomer with inclusion Split Method and acetone precipitation respectively, obtain corresponding chiral quaternary ammonium salt:
Work as R
6When=3-isobutyl-or benzyl:
Work as R
6During=styroyl:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100442213A CN101560184A (en) | 2008-04-16 | 2008-04-16 | N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100442213A CN101560184A (en) | 2008-04-16 | 2008-04-16 | N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101560184A true CN101560184A (en) | 2009-10-21 |
Family
ID=41219186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100442213A Pending CN101560184A (en) | 2008-04-16 | 2008-04-16 | N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101560184A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775418A (en) * | 2012-06-11 | 2012-11-14 | 中国人民解放军第四军医大学 | Synthesis and application of novel chiral quaternary ammonium salt phase-transfer catalyst |
-
2008
- 2008-04-16 CN CNA2008100442213A patent/CN101560184A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775418A (en) * | 2012-06-11 | 2012-11-14 | 中国人民解放军第四军医大学 | Synthesis and application of novel chiral quaternary ammonium salt phase-transfer catalyst |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103080072B (en) | Preparation can be used for the novel method of the intermediate producing nep inhibitor | |
| Jiang et al. | Asymmetric transfer hydrogenation catalysed by hydrophobic dendritic DACH–rhodium complex in water | |
| JP4718452B2 (en) | Optically active transition metal-diamine complex and method for producing optically active alcohols using the same | |
| Huynh et al. | Synthesis of a new class of ligands derived from isosorbide and their application to asymmetric reduction of aromatic ketones by transfer hydrogenation | |
| Zhou et al. | Camphor-derived C 1-symmetric chiral diamine organocatalysts for asymmetric Michael addition of nitroalkanes to enones | |
| EP1870403A1 (en) | Optically active quaternary ammonium salt having axial asymmetry and process for producing -amino acid and derivative thereof with the same | |
| JP5727127B2 (en) | Asymmetric catalyst and method for producing optically active alcohols using the same | |
| CA2671830C (en) | Catalytic process for asymmetric hydrogenation | |
| EP3045459B1 (en) | Method for preparing intermediate compound of sitagliptin | |
| RU2446154C2 (en) | Sulphonylated diphenylethylene diamines, synthesis method thereof and use in transfer hydrogenation catalysis | |
| CN104804006A (en) | Method for synthesizing chiral Tr*ger's base derivatives | |
| JP2003502296A (en) | Sulfonylamides and carboxamides and their use in asymmetric catalysis | |
| CN103111323B (en) | Chirality N, N-dialkyl-1, 2-diaminocyclohexane catalyst as well as preparation method and application thereof | |
| CN101560184A (en) | N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof | |
| CN101954296B (en) | Chiral catalyst for asymmetric Michael addition reaction and preparation method thereof | |
| JP6065259B2 (en) | Method for producing optically active amines | |
| CN101085770B (en) | Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate | |
| Silva Serra et al. | A comparative study of reactivity and selectivity of chiral diamines and structurally analogous amino alcohol ligands in enantioselective alkylations with diethylzinc | |
| JP3159661B2 (en) | Method for producing optically active alcohols | |
| CN103896826A (en) | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method | |
| CN102167698B (en) | Difunctional thioamide organic micromolecule catalyst, preparation method thereof and application thereof | |
| JP5344523B2 (en) | Catalyst capable of proceeding Strecker reaction stereoselectively, and method for stereoselectively producing an α-amino nitrile derivative using the same | |
| JP4928798B2 (en) | Catalyst for asymmetric synthesis, ligand used therein, and method for producing optically active compound by asymmetric synthesis reaction using them | |
| CN101712656A (en) | Oxazoline schiff base ligands and preparation method thereof | |
| Gonsalves et al. | Approach to a better understanding and modelling of β-pyrrolidinoalcohol ligands for enantioselective alkylation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091021 |