CN1435408A - Process of one-step hydrogenation synthesis of alpha-substd. beta-amino acid - Google Patents
Process of one-step hydrogenation synthesis of alpha-substd. beta-amino acid Download PDFInfo
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- CN1435408A CN1435408A CN 02103259 CN02103259A CN1435408A CN 1435408 A CN1435408 A CN 1435408A CN 02103259 CN02103259 CN 02103259 CN 02103259 A CN02103259 A CN 02103259A CN 1435408 A CN1435408 A CN 1435408A
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Abstract
A one-step hydrogenating process for synthesizing beta-amino acid with substituent at its alpha position includes proportionally feeding aldehyde and ethyl cyanoacetate into flask, adding absolute alcohol, stirring while adding dropwise diethylamine, standing for 3-24 hr, adding water, stirring, filtering, drying, adding Raney Ni, acetic anhydride and sodium acetate, hydrogenating at 50-80 deg.C and 5-8 MPa for 16-24 hr, filtering to remove Raney Ni, evaporating out solvent, adding concentrated sulfuric acid, reflux for 0-16 hr, neutralizing with solution of sodium hydroxide, washing and drying.
Description
Technical field
The invention belongs to the technical field of synthetic alpha-non-natural amino acid, particularly belong to universal synthesis method in the beta-amino acids series of β substd.
Background technology
The natural amino acid of nature formation protein etc. is a-amino acid.Their precursor structure formula is H
2N-CH
2-COOH.Contrast with it, the precursor structure formula of beta-amino acids is NH
2-CH
2-CH
2-COOH.With a-amino acid relatively, many methylene radical between amino and the carboxyl in the beta-amino acids molecule.Hydrogen on the amino acid methylene radical can be replaced by various side chain substituents, and this just makes beta-amino acids have the more structural diversity than a-amino acid.Although beta-amino acids does not participate in constituting crude substance such as protein, this does not also mean that they are not present in occurring in nature fully.For example Wasvisz etc. is at " JACS " nineteen fifty-sevens 79 4524 pages of volumes, and G.A.Helms etc. have reported that some contains the beta-amino acids residue from halobiontic big cyclic polypeptide for 1298 pages at " organic chemistry magazine " 1988 53 volumes; People such as C.Gennari rolled up 227 pages in 1987 28 in " tetrahedron communication ", had reported that some natural antibiotics contains the beta-lactam structure.
Beta-amino acids and derivative thereof are subjected to paying close attention to widely owing to the biological activity of self with in the important application of pharmacy field for a long time.People such as A.F.Spatolade are in 1985 " amino acid whose biological chemistry " (Hall that write, London, 1985) on the 25th page of the chapter 3, think that introducing beta-amino acids in certain position of polypeptide can improve its stability to proteolytic enzyme, and can improve its biological activity.In recent years, B.L.Iverson has found beta polypeptide deuterostrophies structure on " nature " magazine was rolled up 113 pages in 1997 385, and this further causes people's research interest.Expect that they can become some ionic channel and biochemical reaction center in vivo.Because beta polypeptide is difficult for therefore being had than better oral stability of alpha polypeptides and biological activity by common protease hydrolysis.In addition, because in the research of the peptide library of combinatorial chemistry, the synthetic polypeptide mostly is the following oligomer of decapeptide, beta polypeptide can not form stable spirane structure; Contrast with it, just can form stable secondary structure as long as these beta polypeptides contain six residues.This shows that synthetic beta-amino acids can prepare the stable polypeptide class of biologically active, and may cause the discovery of new biologically active medicine.
According to domestic and international report, the synthetic beta-amino acids mainly contains two kinds of structure types at present, promptly at general structure NH
2-CHR
β-CHR
αAmong-the COOH, substituent R
αAnd substituent R
βLay respectively at the α position and the β position of beta-amino acids.R
αAnd R
βCan be respectively alkyl, branched-chain alkyl, cycloalkyl, aromatic base, be with various substituent aromatic bases, heterocyclic radical, be with various substituent heterocyclic radicals etc.The synthetic report of relevant beta-amino acids mainly concentrates on the beta-amino acids of β substd, and synthetic method is various, has many documents can be for reference.
This patent only relates to substituent beta-amino acids on the α position.Yet relevant beta-amino acids at the β substd synthetic can see the few of document.Have only following a few example report:
With beta-amino acids this as raw material
A) synthetic by hexahydropyrimidine heterocycle intermediate:
People such as E.Juarisiti have reported to be raw material has substituent beta-amino acids on the synthetic β position by hexahydropyrimidine heterocycle intermediate example with the beta-amino acids for 1355 pages at " organic chemistry magazine " 1991 56 volumes:
B) synthetic by the Claisen rearrangement:
W.Knight etc. have reported with the beta-amino acids to be that raw material synthesizes the method that substituent beta-amino acids is arranged by the Claisen rearrangement on the α position for 1812 pages at " chemistry meeting will news flash " 33 volumes in 1989:
Because raw material beta-amino acids itself will just can obtain through many synthesis steps, so above two kinds of methods synthetic as other beta-amino acids, cost is higher, and synthesis step is also complicated.
2. be that raw material is synthetic with β-halo acid esters
People such as I.T.Barnish rolled up 2581 pages in 1993 34 in " tetrahedron communication " and have reported based on β-halo acid esters and secondary amine nucleophilic substitution reaction, again with the organolithium nucleophilic addition(Adn), and beta-amino acids that can be purer at the β substd:
3. adopt the synthetic α of Diels-Alder cycloaddition, α-dibasic beta-amino acids:
People such as A.Avenoza " tetrahedron-asymmetric " nineteen ninety-fives 6 1409 pages of volumes described and utilized that the Diels-Alder cycloaddition is synthetic to have a α, α-two replaces the beta-amino acids of tension link.Present method is particularly suitable for that the α substituted type beta-amino acids that replaces carboxyl is arranged on the synthetic six membered ring:
The synthetic method of above-described beta-amino acids all exists synthesis step many, separates and purification difficult, and needed reagent costs an arm and a leg, and amplifies synthetic problem such as be restricted.
Summary of the invention
In order to overcome above shortcoming, simplify synthesis step, prepare beta substitution type amino acid in a large number, it is raw material with the cyan-acetic ester that the present invention can provide a kind of, by with the condensation reaction of aldehyde, obtain containing the substituent olefin(e) acid of cyano group; Shortening again, a step is reduced ethylene linkage and cyano group simultaneously, after acid hydrolysis, neutralization, filters, and just can obtain the preparation method of beta substitution type beta-amino acids.
Purposes of the present invention: the route that the present invention taked is the universal synthesis method of a series of β substituted type beta-amino acids.Be particularly suitable for having synthetic with the cyclosubstituted beta-amino acids of substituent fragrance in the α position.Present method can be expanded beta-amino acids small molecules storehouse easily and have the beta-amino acids chemical libraries of Fmoc and Boc protecting group.Also be fit to industrial extensive synthetic beta-amino acids.
Advantage of the present invention and effect:
A) the present invention compares with other synthetic methods, and synthetic route is the shortest.
B) simple to operate, can realize one kettle way (" one-pot ") reaction.
C) product is easy to separate from mixture, and by product is few.
D) raw material, catalyzer obtain easily, do not need expensive special reagent.
E) catalyzer prepares easily and reclaims, and can use repeatedly after the activation.
F) use hydrogen to be reductive agent, in autoclave pressurization can one the step reduce ethylene linkage and cyano group simultaneously, do not bring impurity into.
H) the present invention can synthesize the beta-amino acids series at the α substd that document is seldom reported easily, can expand the chemical libraries of beta-amino acids very easily.
I) on the basis of present method, can form plant-scale preparation.
The concrete synthetic route of the present invention is as follows:
R can be respectively alkyl, branched-chain alkyl, cycloalkyl, aromatic base, is with various substituent aromatic bases, heterocyclic radical, be with various substituent heterocyclic radicals.
The present invention specifically carries out according to following steps: 1. by molar part, with ethyl cyanacetate (this last equal proportion of aldehyde and ester group of 29～71 parts aldehyde and 31～71 parts; As the mole number with aldehyde is 100 parts, the scope of ethyl cyanacetate mole number is 97 parts～107 parts) join in the flask, add 70～170 parts of dehydrated alcohols, stir and drip 1.6～9.5 parts of diethylamine down, place 3～24 hours (place the sufficiently long time, help solid and separate out).Add entry, stir, filter, oven dry obtains solid, productive rate 68～93%.2. get 15～27 parts of the raw materials that obtain above, add 12～17 parts of Raney nickel, 423 parts and 14～32 parts sodium-acetates of acetic anhydride.Exhausted air 1～2 time.Be warmed up to 40～60 ℃, stir hydrogenation 12～24 hours (till gauge pressure does not descend) at 5～8MPa.Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 180～300 parts of concentrated hydrochloric acids, back hydrolysis 12～16 hours.The underpressure distillation demineralizing acid cools off while hot, is neutralized to neutrality with sodium hydroxide solution, use sodium carbonate solution again instead and regulate pH to 8.0～9.5 (faint alkalescence), with the water-bath cooling, place 2～12 hours (having enough precipitations to separate out), filter, filter cake washs secondary with less water, use ethyl acetate (an amount of, as to divide three times) washing again, drying, obtain white powder, productive rate 35-82%.
The evaluation of means such as that all products have all passed through is infrared, nuclear-magnetism.On infrared spectrum, (unit is cm to the characteristic absorbance of the ethylene linkage that condensation forms
-1, down together) and about 3020 (medium tenacity); And for the characteristic absorbance of carboxyl, olefin(e) acid has extremely strong bimodal between 1690-1720; After being reduced, then move to about 1760 and 1420, intensity also weakens to some extent.For nuclear-magnetism, the chemical shift of ethylene linkage hydrogen in this interval, seldom has other interference between 6-7, so unusual feature; After hydrogenation finished, the chemical shift of ethylene linkage hydrogen disappeared; Still have ethylene linkage to exist as also occurring, illustrating, even can calculate hydrogenant productive rate according to the proportional meter of integration.
Embodiment:
Embodiment 1
71 parts of phenyl aldehydes (proportion 1.045, molecular formula C
7H
6O, molecular weight 106.11) and 71 parts of ethyl cyanacetates (proportion 1.06, molecular formula C
5H
7NO
2, molecular weight 113.11) join in the flask, add 67 parts of dehydrated alcohols, add 2.8 parts of diethylamine, place 24 hours (must place the sufficiently long time, otherwise not have solid to separate out).Add 555 parts of water and stir, filter, oven dry obtains 48 parts of white solids, (molecular formula C
12H
11NO
2, molecular weight 201.22), productive rate 68%.
Get 21 parts of (molecular formula C of raw material
12H
11NO
2, molecular weight 201.22), add 14 parts of Raney nickel, 423 parts of acetic anhydride and 14 parts of sodium-acetates.Exhausted air 2 times.Be warmed up to 50 ℃, stir hydrogenation 16 hours (no longer descending) to gauge pressure at 5MPa.Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 300 parts of concentrated hydrochloric acids, back hydrolysis 12 hours.The underpressure distillation demineralizing acid cools off while hot, is neutralized to neutrality with sodium hydroxide solution, use sodium carbonate solution again instead and regulate pH to 8～9 (faint alkalescence), with the water-bath cooling, placed 12 hours, filter, filter cake washs secondary with 50 ml waters, use ethyl acetate (102 parts are divided three times) washing again, drying, obtain 11 parts of white powders, (molecular formula C
10H
13NO
2, molecular weight 179.21), productive rate 52%.
Embodiment 2
50 parts of phenyl aldehydes (proportion 1.045, molecular formula C
7H
6O, molecular weight 106.11) and 50 parts of ethyl cyanacetates (proportion 1.06, molecular formula C
5H
7NO
2, molecular weight 113.11) join in the flask, add 67 parts of dehydrated alcohols, stir down and drip 9.5 parts of diethylamine, placed 3 hours.Add 555 parts of water, stir, filter, oven dry obtains 44 parts of solids, (molecular formula C
12H
11NO
2, molecular weight 201.22), productive rate 88%.
Get 15 parts of (molecular formula C of raw material
12H
11NO
2, molecular weight 201.22), add 12 parts of Raney nickel, 423 parts of acetic anhydride and 14 parts of sodium-acetates.Exhausted air 2 times.Be warmed up to 60 ℃, 7MPa stirs about 16 hours of hydrogenation (gauge pressure no longer descends).Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 180 parts of concentrated hydrochloric acids, back hydrolysis 12 hours.The underpressure distillation demineralizing acid cools off while hot, is neutralized to neutrality with sodium hydroxide solution, use sodium carbonate solution again instead and regulate pH to 8～9 (faint alkalescence), with the water-bath cooling, placed 2 hours, filter, filter cake is with 277 parts of water washing secondaries, use ethyl acetate (102 parts are divided three times) washing again, drying, obtain 11 parts of yellow solids, (molecular formula C
10H
13NO
2, molecular weight 179.21), productive rate 73%.
Embodiment 3
3 of 66 parts of recrystallizations, 4-dichlorobenzaldehyde (molecular formula C
7H
4OCl
2, molecular weight 175.01) and 66 parts of ethyl cyanacetate (proportions 1.06; Molecular formula C
5H
7NO
2, molecular weight 113.11) join in the flask, add 170 parts of dehydrated alcohols, stir down and drip 9.5 parts of diethylamine, placed 6 hours.Filter, with the small amount of ethanol washing, oven dry obtains 56 parts of white solids, (molecular formula C
12H
9NO
2Cl
2, molecular weight 270.11), productive rate 85%.
Get 22 parts of (molecular formula C of raw material
12H
9NO
2Cl
2, molecular weight 270.11), add 17 parts of Raney nickel, 400 milliliters of acetic anhydride and 27 gram sodium-acetates.Exhausted air 2 times.Be warmed up to 50 ℃, stir about 24 hours of hydrogenation (gauge pressure no longer descends).Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 240 parts of concentrated hydrochloric acids, back hydrolysis 16 hours.The underpressure distillation demineralizing acid cools off while hot, is neutralized to neutrality with sodium hydroxide solution, use sodium carbonate solution again instead and regulate pH to 8～9 (faint alkalescence), with the water-bath cooling, placed 6 hours, filter, filter cake is with 277 parts of water washing secondaries, use ethanol again: solution (51: 51 parts are divided three times) the heat washing of ethyl acetate=1: 1, drying, obtain 18 parts of white powders, (molecular formula C
10H
11NO
2Cl
2, molecular weight 248.10), productive rate 82%.
Embodiment 4
32 parts of p-tolyl aldehyde (proportion 1.061,38.20 grams; Molecular formula C
8H
8O, molecular weight 120.15) with 31 parts of ethyl cyanacetates (proportion 1.06; Molecular formula C
5H
7NO
2, molecular weight 113.11) join in the flask, add 67 parts of dehydrated alcohols, stir down and drip 1.6 parts of diethylamine were placed 24 hours.Add 277 parts of water, stir, filter, oven dry obtains 27 parts of white solid (molecular formula C
13H
13NO
2, molecular weight 215.25), productive rate 87%.
Get 27 parts of (molecular formula C of raw material
13H
13NO
2, molecular weight 215.25), add 12 parts of Raney nickel, 423 parts of acetic anhydride and 14 parts of sodium-acetates.Exhausted air 2 times.Be warmed up to 40 ℃, 8MPa stirs about 20 hours of hydrogenation (gauge pressure no longer descends).Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 300 parts of concentrated hydrochloric acids, back hydrolysis 12 hours.Hydrochloric acid is removed in underpressure distillation while hot, cooling is neutralized to neutrality with sodium hydroxide solution, uses sodium carbonate solution again instead and regulates pH to 8～9 (faint alkalescence), cool off with water-bath, placed 4 hours, and filtered, filter cake is with 277 parts of water washing secondaries, use (102 parts of ethyl acetate again, divide three times) washing, drying obtains 12 parts of white powder (molecular formula C
11H
15NO
2, molecular weight 193.24), productive rate 44%.
Embodiment 5
30 parts of 4-chloro-benzaldehyde (molecular formula C
7H
5OCl, molecular weight 140.56) and 31 parts of ethyl cyanacetates (proportion 1.06, molecular formula C
5H
7NO
2, molecular weight 113.11) join in the flask, add 67 parts of dehydrated alcohols, stir down and drip 1.6 parts of diethylamine, placed 24 hours.Add 277 parts of water, filter, oven dry obtains 27 parts of white solids, weighs 64 gram (molecular formula C
12H
10NO
2Cl, molecular weight 235.66), productive rate 90%.
Get 18 parts of (molecular formula C of raw material
12H
10NO
2Cl, molecular weight 235.66), adds 17 parts of Raney nickel, 423 milliliters of acetic anhydride and 12 gram sodium-acetates.Exhausted air 1 time.Be warmed up to 50 ℃, 5MPa stirs about 16 hours of hydrogenation (gauge pressure no longer descends).Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 300 parts of concentrated hydrochloric acids, back hydrolysis 12 hours.Hydrochloric acid is removed in underpressure distillation while hot, cooling is neutralized to neutrality with sodium hydroxide solution, uses sodium carbonate solution again instead and regulates pH to 8～9 (faint alkalescence), cool off with water-bath, placed 6 hours, and filtered, filter cake washs secondaries with 277 parts of ml waters, use (102 parts of ethyl acetate again, divide three times) washing, drying obtains 13 parts of white powder (molecular formula C
10H
12NO
2Cl, molecular weight 213.66), productive rate 72%.
Embodiment 6
29 parts of o-chlorobenzaldehydes (proportion 1.25, molecular formula C
7H
5OCl, molecular weight 140.56) (proportion 1.06,34.98 restrains with 33 milliliters of ethyl cyanacetates; Molecular formula C
5H
7NO
2, molecular weight 113.11,0.31 mol) join in the flask, add 67 parts of dehydrated alcohols, stir down and drip 1.6 parts of diethylamine, placed 24 hours.Filter, oven dry obtains 27 parts of white solids, (molecular formula C
12H
10NO
2Cl, molecular weight 235.66), productive rate 93%.
Get 20 parts of (molecular formula C of raw material
12H
10NO
2Cl, molecular weight 235.66), add 14 parts of Raney nickel, 423 parts of acetic anhydride and 14 parts of sodium-acetates.Exhausted air 2 times.Be warmed up to 55 ℃, 8MPa stirs about 16 hours of hydrogenation (gauge pressure no longer descends).Take out reaction mixture, leach catalyzer, steaming desolventizes, and residuum adds 300 parts of concentrated hydrochloric acids, back hydrolysis 12 hours.Hydrochloric acid is removed in underpressure distillation while hot, cooling is neutralized to neutrality with sodium hydroxide solution, uses sodium carbonate solution again instead and regulates pH to 8～9 (faint alkalescence), cool off with water-bath, placed 4 hours, and filtered, filter cake is with 277 parts of water washing secondaries, use (102 parts of ethyl acetate again, divide three times) washing, drying obtains 7 parts of white powder (molecular formula C
10H
12NO
2Cl, molecular weight 213.66), productive rate 35%.
Claims (2)
1, a kind of synthetic method of beta-amino acids of α position replacement is characterized in that described synthetic method is a step hydrogenation synthesis method, and synthetic route is as follows:
In the formula: R is an alkyl, branched-chain alkyl, cycloalkyl, aromatic base, be with various substituent aromatic bases, heterocyclic radical, be with various substituent heterocyclic radicals, concrete synthetic method step is in the following order carried out: (1) is by molar part, the ethyl cyanacetate of 29～71 parts aldehyde and 31～71 parts is joined in the flask, add 70～170 parts of dehydrated alcohols, stir and drip 1.6～9.5 parts of diethylamine down, placed 3～24 hours, add entry, stir, filter, oven dry, obtain having the olefin(e) acid ester of cyano group, (2) 15～27 parts of above-mentioned olefin(e) acid esters that has cyano group that obtains are added 12～17 parts of Raney nickel, 423 parts of acetic anhydride and 14～32 parts of sodium-acetates were 40～60 ℃ and 5～8MPa stirring hydrogenation 16～24 hours.Take out reaction mixture, leach Raney nickel, residuum adds 180～300 parts of concentrated hydrochloric acids, back hydrolysis 12～16 hours, be neutralized to neutrality with sodium hydroxide solution, use sodium carbonate solution again instead and regulate pH to 8.0～9.5,, placed 2～12 hours with the water-bath cooling, filter, washing, drying obtains the beta-amino acids white powder that the α position replaces.
2, the synthetic method of the beta-amino acids of α position replacement according to claim 1 is characterized in that described aldehyde is phenyl aldehyde, 3, and 4-dichlorobenzaldehyde, p-tolyl aldehyde, 4-chloro-benzaldehyde or o-chlorobenzaldehyde.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006059801A1 (en) * | 2004-12-02 | 2006-06-08 | Asubio Pharma Co., Ltd. | 7-membered ring compound, process for producing the same, and medicinal use thereof |
| WO2007139230A1 (en) * | 2006-05-31 | 2007-12-06 | Asubio Pharma Co., Ltd. | Seven-membered ring compound, production method thereof and pharmaceutical use thereof |
| CN103998618A (en) * | 2011-12-19 | 2014-08-20 | 住友化学株式会社 | Method for producing optically-active alpha-substituted-beta-amino acid |
-
2002
- 2002-02-01 CN CN 02103259 patent/CN1435408A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006059801A1 (en) * | 2004-12-02 | 2006-06-08 | Asubio Pharma Co., Ltd. | 7-membered ring compound, process for producing the same, and medicinal use thereof |
| JPWO2006059801A1 (en) * | 2004-12-02 | 2008-06-05 | アスビオファーマ株式会社 | 7-membered ring compounds and their production and pharmaceutical use |
| CN101160290B (en) * | 2004-12-02 | 2011-01-19 | 第一三共株式会社 | 7-membered ring compound, process for producing the same, and medicinal use thereof |
| RU2448099C2 (en) * | 2004-12-02 | 2012-04-20 | Дайити Санкё Компани, Лимитед | 7-member cyclic compounds, synthesis methods thereof and pharmaceutical application thereof |
| JP5004590B2 (en) * | 2004-12-02 | 2012-08-22 | 第一三共株式会社 | 7-membered ring compounds and their production and pharmaceutical use |
| US8507714B2 (en) | 2004-12-02 | 2013-08-13 | Daiichi Sankyo Company, Limited | 7-membered ring compound and method of production and pharmaceutical application thereof |
| WO2007139230A1 (en) * | 2006-05-31 | 2007-12-06 | Asubio Pharma Co., Ltd. | Seven-membered ring compound, production method thereof and pharmaceutical use thereof |
| US8049006B2 (en) | 2006-05-31 | 2011-11-01 | Daiichi Sankyo Company, Limited | 7-membered ring compound and method of production and pharmaceutical application thereof |
| CN103998618A (en) * | 2011-12-19 | 2014-08-20 | 住友化学株式会社 | Method for producing optically-active alpha-substituted-beta-amino acid |
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