CN102320908A - A kind of preparation method of beta-amino acids or derivatives thereof - Google Patents
A kind of preparation method of beta-amino acids or derivatives thereof Download PDFInfo
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- CN102320908A CN102320908A CN201110163222A CN201110163222A CN102320908A CN 102320908 A CN102320908 A CN 102320908A CN 201110163222 A CN201110163222 A CN 201110163222A CN 201110163222 A CN201110163222 A CN 201110163222A CN 102320908 A CN102320908 A CN 102320908A
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Abstract
The invention discloses a kind of preparation method of beta-amino acids or derivatives thereof.Beta-amino acids according to the invention comprises the beta-amino acids of alpha-substitution and the beta-amino acids of beta substitution.Wherein, The reduction reaction takes place through α-amine methylacrylic acid (ester) of not protecting and protecting and obtains in the beta-amino acids or derivatives thereof of alpha-substitution under the effect of metal-salt-hydroborate, the beta-amino acids or derivatives thereof of beta substitution through the beta-amido vinylformic acid of protecting (ester) the reduction reaction takes place under the effect of metal-salt-hydroborate and obtains.The inventive method has that selectivity height, reaction conditions are gentle, simple to operate, the advantage of economic security.
Description
Technical field
The present invention relates to the compound field, be specifically related to a kind of preparation method of beta-amino acids or derivatives thereof.
Background technology
Beta-amino acids more and more receives the concern of academia and industry member because of its biology and pharmaceutical activity widely.With the beta-peptide that it is constructed, have very high enzyme stability, and have interesting three-dimensional structure (
Acc. Chem. Res. 1998,
31, 173. Juaristi, E.; Lopez-Ruiz, H.
Curr. Med. Chem. 1999,
6, 983.).Many bioactive compoundss with pharmacologically active have all comprised the structural unit of beta-amino acids, for example taxol (Ojima, I.; Lin, S.N.; Wang, T.
Curr. Med. Chem. 1999,
6, 927.) and dolastatins (
J. Am. Chem. Soc. 1997,
119, 2111.).
Beta-amino acids can be divided three classes, and one type is the beta-amino acids of alpha-substitution, and one type is the beta-amino acids of beta substitution, and also having one type is α, and the beta-amino acids of beta substitution (is called β again
2,3-amino acid), the three is with a wide range of applications.The midbody of the antifungal drug croptophycin-1 that the beta-amino acids application example of alpha-substitution such as Merck & Co., Inc. (MERCK) find (
J. Nat. Prod. 1997,
60, 302.;
J. Nat. Prod. 2004,
67, 1403.;
J. Ind. Microbiol. 1990,
5, 113.), (WO 2004/076053) such as important intermediate of a kind of PDF enzyme inhibitors of Novartis Co.,Ltd (NOVARTIS) synthetic.But since beta-amino acids in the abundance of occurring in nature much smaller than a-amino acid, the kind of existence is limited, and the separation and Extraction difficulty, is difficult to satisfy the research needs, so synthetic beta-amino acids or derivatives thereof just becomes a research focus gradually.
Summary of the invention
The object of the present invention is to provide a kind of metal-salt that uses cheapness as catalyzer, hydroborate such as NaBH
4Deng as reductive agent, low cost, high yield, dehydroamino acid and the verivate thereof of reducing simple to operate, the method for the beta-amino acids or derivatives thereof of preparation alpha-substitution and the beta-amino acids or derivatives thereof of beta substitution.
The object of the invention is achieved through following technical scheme:
The preparation method of the beta-amino acids or derivatives thereof of alpha-substitution; Be to be dissolved in the organic solvent through α-amine methylacrylic acid (ester) and the metal-salt of not protecting and protecting; After the stirring at room, add the hydroborate reaction, obtain the beta-amino acids or derivatives thereof of alpha-substitution.
The structural formula of the beta-amino acids or derivatives thereof of the alpha-substitution that method for preparing obtains is suc as formula shown in (
):
Formula (
);
Wherein, R
1Be H, C
1-10Alkyl, C
3-7Naphthenic base, heterocycle, aryl and substituted aryl; R
2, R
3Independent respectively is H, ethanoyl, formyl radical, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzoyl-, p-toluenesulfonyl, trifluoroacetyl group, benzyloxy, methoxyl group, oxyethyl group, benzyl, R
2, R
3Also can unite and be phthalimide-based; R
4Be H, C
1-10Alkyl, C
3-7Naphthenic base, heterocycle, aryl and substituted aryl.
The preparation method of the beta-amino acids or derivatives thereof of beta substitution is to be dissolved in the organic solvent through beta-amido vinylformic acid (ester) and the metal-salt of protecting, and after the stirring at room, adds the hydroborate reaction, obtains the beta-amino acids or derivatives thereof of beta substitution.
The structural formula of the beta-amino acids or derivatives thereof of the beta substitution that method for preparing obtains is suc as formula shown in (
):
Formula (
);
Wherein, R
5Be H, C
1-10Alkyl, C
3-7Naphthenic base, heterocycle, aryl and substituted aryl; R
6, R
7Independent respectively is H, ethanoyl, formyl radical, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzoyl-, p-toluenesulfonyl, trifluoroacetyl group, benzyloxy, methoxyl group, oxyethyl group, benzyl, R
6, R
7Also can unite and be phthalimide-based; R
8Be H, C
1-10Alkyl, C
3-7Naphthenic base, heterocycle, aryl and substituted aryl.
The preparation method of the beta-amino acids or derivatives thereof of above-mentioned alpha-substitution and the beta-amino acids or derivatives thereof of beta substitution can be suc as formula shown in (
):
Formula (
).
As a kind of preferred version, among the above-mentioned preparation method, said metal-salt be nickeliferous, copper, cobalt, aluminium, bismuth, iron metal-salt or with they corresponding compounds that contains crystal water.
As a kind of preferred version, among the above-mentioned preparation method, said hydroborate is NaBH
4, KBH
4, NaBH
3CN or LiBH
4
As a kind of preferred version, among the above-mentioned preparation method, said organic solvent is C
1-10Alcohol, THF, acetone, toluene, chloroform, DMF (N, dinethylformamide), HMPA (hexamethylphosphoric acid triamide) or DMSO (dimethyl-inferior maple) in one or more mixture.
As a kind of preferred version, among the above-mentioned preparation method, the mol ratio of said α-amine methylacrylic acid (ester), metal-salt and hydroborate is 1:0.5 ~ 5:6 ~ 20.
As a kind of preferred version, among the above-mentioned preparation method, the time of said stirring is 5 ~ 10 min.
As a kind of preferred version, among the above-mentioned preparation method, the temperature of said adding hydroborate is-20 ~ 50 ℃.
As a kind of preferred version, among the above-mentioned preparation method, the said post-reacted time of adding hydroborate is 1 ~ 5 h.
Compared with prior art, the present invention has following beneficial effect:
Preparing method of the present invention has the chemo-selective of height, only optionally reduces carbon-carbon double bond, and reaction conditions is gentle, safety simple to operate, and process economy, yield is high.
Embodiment
Come further to explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
Embodiment 1
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E/Z)-α-benzyloxy amine methyl-2-butene acid methyl esters (71 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 63%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.24–7.33?(m,?5H),?5.64?(bs,?1H),?4.66?(s,?2H),?3.66,?(s,?3H),?2.98–3.20?(m,?2H),?2.63–2.72?(m,?1H),?1.50–1.68?(m,?2H),?0.91?(t,?
J?=?7.4?Hz,?3H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ?=?176.7,?138.0,?128.6,?128.5,?128.0,?76.5,?53.8,?51.8,?45.6,?23.8,?12.0。
Embodiment 2
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-beta-phenyl methyl acrylate (90 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then; Methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying filters; Pressure reducing and steaming solvent, residuum column chromatography obtain the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 80%.
1H?NMR?(300?MHz,?CDCl
3):?δ?=?7.12–7.33?(m,?10H),?5.68?(bs,?1H),?4.63?(d,?
J?=?1.5?Hz,?2H),?3.59?(s,?3H),?2.77–3.21?(m,?5H)?。
Embodiment 3
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-β-Chloro-O-Phenyl methyl acrylate (100 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 78%.
1H?NMR?(300?MHz,?CDCl
3):?
δ=?7.22–7.37?(m,?6H),?7.12–7.19?(m,?3H),?5.65?(bs,?1H),?4.64?(d,?
J?=?1.8?Hz,?2H),?3.57?(s,?3H),?2.94–3.22?(m,?5H);?
13C?NMR?(100?Hz,?CDCl
3):?
δ?=?174.9,?137.8,?136.6,?134.2,?131.2,?129.7,?128.5,?128.4,?128.1,?127.8,?126.8,?76.3,?53.4,?51.6,?43.9,?34.0。
Embodiment 4
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-β-m-chloro phenylacrylic acid methyl esters (100 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 76%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.17–7.29?(m,?5H),?7.05–7.13?(m,?3H),?6.90–6.97?(m,?1H),?5.64?(bs,?1H),?4.56?(d,?
J?=?1.6?Hz,?2H),?3.52?(s,?3H),?2.56–3.01?(m,?5H);?
13C?NMR?(100?Hz,?CDCl
3):?
δ?=?174.7,?140.9,?137.7,?134.3,?129.7,?129.1,?128.5,?128.4,?127.9,?127.1,?126.7,?76.3,?53.1,?51.7,?45.4,?35.8。
Embodiment 5
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-β-rubigan methyl acrylate (100 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 72%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.27–7.34?(m,?5H),?7.22?(d,?
J?=?7.9?Hz,?2H),?7.05?(d,?
J?=?7.9?Hz,?2H),?5.70?(bs,?1H),?4.63?(d,?
J?=?1.1?Hz,?2H),?3.58?(s,?3H),?2.74–3.19?(m,?5H);?
13C?NMR?(100?Hz,?CDCl
3):?
δ=?174.7,?137.7,?137.3,?132.3,?130.3,?128.6,?128.5,?128.4,?127.9,?76.3,?53.2,?51.7,?45.6,?35.5。
Embodiment 6
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-β-p-methylphenyl methyl acrylate (95 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 94%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.17–7.30?(m,?5H),?6.99-7.06?(m,?4H),?5.67?(bs,?1H),?4.62?(d,?
J?=?1.5?Hz,?2H),?3.57?(s,?3H),?2.71–3.18?(m,?5H),?2.29?(s,?3H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ?=?175.2,?138.0,?136.1,?135.8,?129.4,?129.0,?128.7,?128.6,?128.0,?76.5,?53.5,?51.9,?46.1,?36.2。
Embodiment 7
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-ethanamide methyl-beta-phenyl methyl acrylate (70 mg, 0.3 mmol), ethanol (3 mL), NiCl
26H
2O (36 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 82%.
1H?NMR?(300?MHz,?CDCl
3):?
δ=?7.07–7.22?(m,?5H),?5.98?(m,?1H),?3.57?(s,?1H),?3.41–3.47?(m,?1H),?3.24–3.31?(m,?1H),?2.84–2.91?(m,?2H),?2.72–2.78?(m,?1H),?1.86?(s,?3H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ=?174.8,?170.3,?138.1,?128.8,?128.6,?126.7,?51.8,?46.7,?40.3,?36.1,?23.2。
Embodiment 8
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-ethanamide methyl-β-rubigan methyl acrylate (80 mg, 0.3 mmol), ethanol (3 mL), NiCl
26H
2O (36 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 87%.
1H?NMR?(300?MHz,?CDCl
3):?
δ=?7.04–7.25?(m,?4H),?6.20?(bs,?1H),?3.59?(s,?3H),?3.45–3.48?(m,?1H),?3.27–3.35?(m,?1H),?2.84–2.95?(m,?2H),?2.72–2.82?(m,?1H),?1.89?(s,?3H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ=?174.6,?170.2,?138.1,?130.1,?128.7,?126.6,?51.7,?46.7,?40.3,?36.0,?23.1。
Embodiment 9
The preparation method is suc as formula shown in (
):
Formula (
).
Under the room temperature, in 25 mL round-bottomed flasks, add α-BM methyl-methyl acrylate (66 mg, 0.3 mmol), methyl alcohol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 76%.
1H?NMR?(300?MHz,?CDCl
3):?
δ=?7.72–7.76?(m,?2H),?7.36–7.49?(m,?3H),?6.88?(bs,?1H),?4.14?(td,?
J 1 ?=?7.1?Hz,?
J 2 ?=?0.9?Hz,?2H),?3.65–3.73?(m,?1H),?3.45–3.54?(m,?1H),?2.74–2.85?(m,?1H),?1.22–1.28?(m,?6H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ?=?175.8,?167.6,?134.6,?131.6,?128.7,?127.1,?61.1,?42.4,?39.8,?15.3,?14.6。
Embodiment 10
The preparation method is suc as formula shown in (XIII):
Formula (XIII).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-phthalimide methyl-beta-phenyl methyl acrylate (96 mg, 0.3 mmol), ethanol (3 mL), BiCl
3(47 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 73%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.80?(dd,?
J?=?5.2,?3.2?Hz,?2H),?7.69–7.72?(m,?2H?),?7.13–7.25?(m,?5H),?3.98?(dd,?
J?=?13.8,?8.2?Hz,?1H),?3.84?(dd,?
J?=?14.0,?6.0?Hz,?1H),?3.58?(s,?3H),3.28?(m,?1H),?3.05?(dd,?
J?=?13.2,?7.6?Hz,1H),?2.83?(dd,?
J?=?14.0,?6.4?Hz,?1H);?
13C?NMR?(75?Hz,?CDCl
3):?
δ=?173.9,?168.7,?138.7,?134.7,?132.5,?129.4,?129.1,?127.2,?124.0,?52.7,?46.4,?40.2,?36.6。
Embodiment 11
Formula (X
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-α-benzyloxy amine methyl-beta-phenyl vinylformic acid (86 mg, 0.3 mmol), ethanol (3 mL), NiCl
26H
2O (36 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-amino acids of corresponding pure alpha-substitution.Productive rate is 80%.
1H?NMR?(300?MHz,?CDCl
3):?δ?=?7.16–7.38?(m,?10H),?5.73?(bs,?1H),?4.69?(d,?
J?=?1.7?Hz,?2H),?2.69–3.18?(m,?5H)。
Embodiment 12
The beta-aminoacid-derivatives of some alpha-substitution that obtain by the foregoing description sees the following form:
| No | R 1 | R 2 | R 3 | R 4 | Productive rate % |
| 1 | 2-FC 6H 4 ( E) | OBn | H | Me | 71 |
| 2 | 2-BrC 6H 4 ? ( E) | OBn | H | Me | 77 |
| 3 | 3-FC 6H 4 ( E) | OBn | H | Me | 73 |
| 4 | 3-BrC 6H 4 ( E) | OBn | H | Me | 81 |
| 5 | 3-MeOC 6H 4 ( E) | OBn | H | Me | 67 |
| 6 | 4-FC 6H 4 ( E) | OBn | H | Me | 76 |
| 7 | 4-BrC 6H 4 ? ( E) | OBn | H | Me | 81 |
| 8 | 4-MeOC 6H 4 ( E) | OBn | H | Me | 87 |
| 9 | 2-Naphthyl ( E) | OBn | H | Me | 75 |
| 10 | Phenylethyl（ E/Z） | OBn | H | Me | 71 |
| 11 | Cyclohexyl （ E/Z） | OBn | H | Me | 69 |
| 12 | 2-Furyl ( E)? | OBn | H | Me | 67 |
| 13 | 2-Thienyl ( E) | OBn | H | Me | 74 |
| 14 | 4-Pyridyl ? ( E) | OBn | H | Et | 65 |
| 15 | Ph ? ( Z) | OBn | H | Me | 65 |
| 16 | 2-FC 6H 4 ( Z) | OBn | H | Me | 59 |
| 17 | 4-FC 6H 4 ( Z) | OBn | H | Me | 63 |
| 18 | 3-FC 6H 4 ( E) | Ac | H | Me | 78 |
| 19 | 4-FC 6H 4 ( E) | Ac | H | Me | 83 |
| 20 | 3-ClC 6H 4 ( E) | Ac | H | Me | 85 |
| 21 | 2-BrC 6H 4 ? ( E) | Ac | H | Me | 89 |
Embodiment 13
The preparation method is suc as formula shown in (X
):
Formula (X
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-β-acetamido-β-ethylacrylic acid methyl esters (59 mg, 0.3 mmol), ethanol (3 mL), NiCl
26H
2O (36 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 88%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?6.14?(bs,?1H),?4.28?(m,?1H),?3.63?(s,?3H),?2.47?(m,?3H),?1.90?(s,?3H),?1.16?(d,?
J?=?6.81?Hz,?3H).
Embodiment 14
The preparation method is suc as formula shown in (X
):
Formula (X
).
Under the room temperature, in 25 mL round-bottomed flasks, add (
E)-β-acetamido-beta-phenyl methyl acrylate (66 mg, 0.3 mmol), ethanol (3 mL), NiCl
26H
2O (36 mg, 0.15 mmol) stirred 5 minutes, and 0 ℃ slowly adds NaBH down
4(69 mg, 1.8 mmol) added afterreaction 1 hour; In above-mentioned reaction solution, add saturated aqueous ammonium chloride (15 mL) then, methylene dichloride (20 mL * 3) extraction, anhydrous magnesium sulfate drying; Filter; The pressure reducing and steaming solvent, the residuum column chromatography obtains the beta-aminoacid-derivatives of corresponding pure alpha-substitution.Productive rate is 82%.
1H?NMR?(300?MHz,?CDCl
3):?
δ?=?7.18–7.27?(m,?5H),?6.65?(bs,?1H),?5.34?(m,?1H),?3.53?(s,?3H),?2.76–2.83?(m,?2H),?1.92?(s,?3H)。
Claims (8)
1. the preparation method of a beta-amino acids or derivatives thereof is characterized in that said beta-amino acids comprises the beta-amino acids of alpha-substitution and the beta-amino acids of beta substitution; The beta-amino acids or derivatives thereof of said alpha-substitution is to be dissolved in the organic solvent through the α that does not protect and protect-amine methylacrylic acid or its ester and metal-salt; After the stirring at room; Add the hydroborate reaction, obtain the beta-amino acids or derivatives thereof of corresponding alpha-substitution; The beta-amino acids or derivatives thereof of said beta substitution is to be dissolved in the organic solvent through the beta-amido vinylformic acid of not protecting and protecting or its ester and metal-salt; After the stirring at room; Add the hydroborate reaction, obtain the beta-amino acids or derivatives thereof of corresponding beta substitution.
2. the preparation method of beta-amino acids or derivatives thereof according to claim 1, it is characterized in that said metal-salt be nickeliferous, copper, cobalt, aluminium, bismuth, iron metal-salt or with they corresponding compounds that contains crystal water.
3. the preparation method of beta-amino acids or derivatives thereof according to claim 1 is characterized in that said hydroborate is NaBH
4, KBH
4, NaBH
3CN or LiBH
4
4. the preparation method of beta-amino acids or derivatives thereof according to claim 1 is characterized in that said organic solvent is C
1-10Alcohol, THF, acetone, toluene, chloroform, DMF (N, dinethylformamide), HMPA (hexamethylphosphoric acid triamide) or DMSO (dimethyl-inferior maple) in one or more mixture.
5. the preparation method of beta-amino acids or derivatives thereof according to claim 1 is characterized in that the mol ratio of said α-amine methylacrylic acid (ester), metal-salt and hydroborate is 1:0.5 ~ 5:6 ~ 20.
6. the preparation method of beta-amino acids or derivatives thereof according to claim 1, the time that it is characterized in that said stirring is 5 ~ 10 min.
7. the preparation method of beta-amino acids or derivatives thereof according to claim 1 is characterized in that the temperature of said adding hydroborate is-20 ~ 50 ℃.
8. the preparation method of beta-amino acids or derivatives thereof according to claim 1 is characterized in that the said post-reacted time of adding hydroborate is 1 ~ 5 h.
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| CN109761988A (en) * | 2019-01-17 | 2019-05-17 | 深圳市第二人民医院 | The preparation method for treating the drug sitagliptin of diabetes |
| CN114315945A (en) * | 2020-09-28 | 2022-04-12 | 四川澄华生物科技有限公司 | Impurity removal method for cholestanic acid and derivatives thereof |
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| CN114315945A (en) * | 2020-09-28 | 2022-04-12 | 四川澄华生物科技有限公司 | Impurity removal method for cholestanic acid and derivatives thereof |
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