CN105037210A - Alpha,beta-dehydrogenated-alpha-amino acid synthesis method - Google Patents

Alpha,beta-dehydrogenated-alpha-amino acid synthesis method Download PDF

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Publication number
CN105037210A
CN105037210A CN201510278107.7A CN201510278107A CN105037210A CN 105037210 A CN105037210 A CN 105037210A CN 201510278107 A CN201510278107 A CN 201510278107A CN 105037210 A CN105037210 A CN 105037210A
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China
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amino acid
α
dehydrogenation
β
synthetic method
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CN201510278107.7A
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Chinese (zh)
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杨永青
陆征
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江苏大学
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Abstract

The present invention relates to an alpha,beta-dehydrogenated-alpha-amino acid synthesis method, which is a one-step synthesis method, wherein an amino acid derivative containing beta-hydroxy reacts with an organic base and an aryl sulfonyl compound to prepare the alpha,beta-dehydrogenated-alpha-amino acid. The method of the present invention has characteristics of low cost, mild reaction condition, and simple operation.

Description

The synthetic method of a kind of α, β-dehydrogenation-a-amino acid

Technical field

The invention belongs to Amino acid synthesis field, particularly relate to the synthetic method of a kind of α, β-dehydrogenation-a-amino acid.

Background technology

α, β-dehydroamino acid belongs to the uncoded amino acid of occurring in nature one class, is that some has the integral part of the polypeptide of important biomolecule activity.Mainly comprise dehydroalanine (△ Ala), dehydrogenation butyrine (△ Abu), dehydrogenation α-amino-isovaleric acid (△ Val), dehydrogenation Isoleucine ((E)-△ Ile), dehydrogenation aspartic acid ((E)-△ Asp) etc.(table 1).

There is main α in table 1. occurring in nature, β-dehydroamino acid.

Wherein, dehydroalanine (△ Ala)/dehydrogenation butyrine (△ Abu) is the comparatively simple structure of central structure, exist comparatively extensive at occurring in nature, such as, nisin (the Nisin of Lactococcus lactis secretion, nisin) in just containing two dehydroalanine (△ Ala) residues and a dehydrogenation butyrine (△ Abu), be widely used as food preservatives now.In addition, it also Chang Zuowei synthesize the starting raw material of other comparatively complicated dehydroamino acids, the document " Aring-closingmetathesisapproachtocyclicalpha; beta-dehydroaminoacids " of the people such as such as Rutjes once reported with △ Ala as raw material, ring-type five yuan or hexa-atomic α, β-dehydroamino acid (formula 1) is obtained by alkene cultural care (RCM).

The people such as Ferreira in document " SynthesisofsubstitutedoxazolesfromN-acyl-beta-hydroxyami noacidderivatives ", with (Z)-△ Abu be starting raw material in the basic conditions, at I 2effect under, synthesized Yi Xi Lie oxazole ring compounds (formula 2).

The synthesis report of dehydroalanine (△ Ala)/dehydrogenation butyrine (△ Abu) compounds is also emerged in an endless stream always.Kinoshita group in 2009, is transformed by four steps for starting raw material Jing oxazoline intermediate with N-tertbutyloxycarbonyl-glycine methyl ester, generates the dehydroamino acid of (Z)-configuration.Final step transforms to be needed, under organic bases LHMDS (LiHMDS) effect, according to the different in kind of substrate, to react temperature required scope from-10 DEG C to-100 DEG C not etc.

The people such as Chadrasekaran in 2007 report two step synthesis dehydroamino acid △ Ala and (Z)-△ Abu compounds.The method is that the first step introduces carbobenzoxy-(Cbz) on the free hydroxyl group of O-methyl N-tertbutyloxycarbonyl Serine, and second step uses the salt of wormwood of 2 equivalents to react one hour at 65 DEG C in DMF (DMF), and yield reaches 83%.They found to replace salt of wormwood with tetrabutyl ammonium fluoride (TBAF), accelerated reaction process afterwards, and react under room temperature and only need ten minutes, yield is 80 ~ 90%.

The main limitation that the method exists is when the first step activates beta-hydroxy by introducing carbalkoxy on beta-hydroxy, needs to react 2 to 4 hours under the low temperature of-50 DEG C, thus limits the widespread use of the method.

The people such as Paradisi reported one-step synthesis method α, the method for β-dehydroamino acid, but needed in reaction to use N-fluoroform sulfimide.This reagent is 427.05 yuan/5 grams (Aldrich), expensive, limits the extensive popularization of the method.

In sum, although α, β-dehydroamino acid has more report, from the angle of suitability for industrialized production, still there is the demand of improvement in synthetic route.If can from substrate cheap and easy to get, under mild conditions, synthesize this compounds by succinct step, this will be with a wide range of applications, and produce huge economic benefit.

Summary of the invention

For Shortcomings in prior art, the invention provides the synthetic method of a kind of α, β-dehydrogenation-a-amino acid, the method from substrate cheap and easy to get, gentleness alkaline condition next step synthesis.

The present invention realizes above-mentioned technical purpose by following technique means.

A kind of α, the synthetic method of β-dehydrogenation-a-amino acid, comprises the steps: that by the N-alkoxycarbonyl amido acid esters containing beta-hydroxy be starting raw material, is dissolved in organic solvent, and under the activation of SULPHURYL CHLORIDE and DMAP, under organic bases effect, stirring reaction at 10 ~ 30 DEG C, through aftertreatment, obtain N-carbalkoxy-O-alkyl-α, β-unsaturated amino acid, yield 50% to 95%, reaction formula is:

Wherein, R is aryl or alkyl, R 1for hydrogen (H) or methyl (Me), R 2for the tertiary butyl ( tbu), benzyl (Bn) or 9-fluorene methyl, R 3for methyl (Me), ethyl (Et), the tertiary butyl ( tbu), allyl group (ally) or benzyl.

The described N-alkoxycarbonyl amido acid esters concentration in organic solvent containing beta-hydroxy is 0.01 ~ 2mol/L.

The described N-alkoxycarbonyl amido acid esters containing beta-hydroxy: SULPHURYL CHLORIDE: DMAP: the ratio of the amount of substance of organic bases is 1:1 ~ 4:0.05 ~ 0.6:1 ~ 20.

The described reaction times is 5 minutes to 48 hours.

Described organic bases is triethylamine, Tributylamine, pyridine, 1,8-diazacyclo [5,4,0] hendecene-7, diisopropyl ethyl amine.

Described organic solvent is methylene dichloride, ethyl acetate, acetonitrile.

Described aftertreatment is: after reaction mixture reaction terminates, add organic solvent diluting, wash three times, collect organic phase, then with saturated common salt washing, finally uses anhydrous sodium sulfate drying.After rotary evaporation of solvent, obtain thick product, column chromatography for separation.

In aftertreatment, described organic solvent is recommended as ethyl acetate, methylene dichloride, ether; Described consumption of organic solvent is every mmole N-carbalkoxy-O-alkoxyamino acid 1 to 50 milliliter.

Beneficial effect of the present invention is:

Compared with existing preparation method, the inventive method has the advantages that cost is inexpensive, mild condition is easy and simple to handle.

Embodiment

Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to this.

Embodiment 1

( +)-N-tertbutyloxycarbonyl serine methylester (219mg, 1mmol) be dissolved in methylene dichloride (5mL), Tosyl chloride (380mg is added successively in solution, 2mmol), DMAP (24mg, 0.1mmol), triethylamine (505mg is slowly instilled at 20 DEG C, 5mmol), then stirring 1 hour is continued, thin-layer chromatography display raw material disappears, add water (5ml) cancellation, concentrating under reduced pressure, removing methylene dichloride, then with extraction into ethyl acetate (30mL*3), organic phase is washed through saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Thick product is obtained after concentrating under reduced pressure.Then by flash column analysis method purifying (eluent is ethyl acetate/petroleum ether=1:20), normal temperature concentrating under reduced pressure, obtain 2-(N-tertbutyloxycarbonyl) urethanes (colourless oil liquid, 85mg, yield 76%). 1HNMR(400MHz,CDCl 3)δ7.02(brs,1H),6.16(s,1H),5.73(d,J=1.2Hz,1H),3.83(s,3H),1.49(s,9H)。

This compound reported in document is colourless oil liquid, 1hNMR (300MHz, CDCl 3) δ 7.02 (brs, 1H), 6.16 (s, 1H), 5.73 (d, J=1.5Hz, 1H), 3.83 (s, 3H), 1.49 (s, 9H).

Embodiment 2

( +)-N-tertbutyloxycarbonyl threonine methyl (92mg, 0.39mmol) be dissolved in acetonitrile (2mL), Tosyl chloride (149mg is added successively in solution, 0.78mmol), DMAP (9mg, 0.08mmol), slowly instillation 1 at 20 DEG C, 8-diazacyclo [5, 4, 0] 11 carbon-7-alkene (300mg, 1.95mmol), then stirring 5 hours is continued, thin-layer chromatography follows the tracks of reaction, after reaction terminates, add water (5mL) cancellation, then be extracted with ethyl acetate (30mL*3), organic phase saturated common salt is washed, anhydrous sodium sulfate drying.Concentrating under reduced pressure, obtains thick product.Then (eluent is ethyl acetate/petroleum ether=1:20) is purified with flash column analysis method, (Z)-2-N-t-butoxycarbonyl amino-2-butylene acid methyl esters (colourless oil liquid is obtained after normal temperature concentrating under reduced pressure, 42mg, yield 50%). 1HNMR(400MHz,CDCl 3)d6.67(q,J=7.2Hz,1H),5.97(brs,1H),3.76(s,3H),1.80(d,J=7.2Hz,3H),1.46(s,9H)。

This compound reported in document is colourless oil liquid, 1hNMR (300MHz, CDCl 3) δ 6.68 (q, J=6.9Hz, 1H), 6.04 (brs, 1H), 3,77 (s, 3H), 1.80 (d, J=6.9Hz, 3H), 1.47 (s, 9H).

Embodiment 3:

( +)-N-tertbutyloxycarbonyl Serine isopropyl ester (247mg, 1mmol) be dissolved in acetonitrile (5mL), Tosyl chloride (380mg is added successively in solution, 2mmol), 4-dimethylamino pyridine (24mg, 0.1mmol), slowly instillation 1 at 20 DEG C, 8-diazacyclo [5, 4, 0] hendecene-7 (760mg, 5mmol), then stirring 17 hours is continued, when thin-layer chromatography display raw material is little, add water (5ml) cancellation, decompression backspin steams, remove acetonitrile, then be extracted with ethyl acetate (30mL*3), organic phase saturated aqueous common salt (30mL) is washed, anhydrous sodium sulfate drying.Concentrating under reduced pressure, obtains thick product.Then (eluent is ethyl acetate/petroleum ether=1:20) is purified with flash column analysis method, normal temperature concentrating under reduced pressure, obtains 2-N-t-butoxycarbonyl amino isopropyl acrylate (colourless oil liquid, 218mg, 0.95mmol, yield 95%). 1HNMR(400MHz,CDCl 3)δ7.04(brs,1H),6.11(s,1H),5.71(d,J=1.2Hz,1H),5.10(sept,J=6.4Hz,1H),1.48(s,9H),1.30(d,J=6.4Hz,6H)。

This compound of bibliographical information is colourless oil liquid, 1hNMR (300MHz, CDCl 3) δ 7.05 (brs, 1H), 6.12 (s, 1H), 5.71 (d, J=1.2Hz, 1H), 5.07 – 5.18 (m, 1H), 1.49 (s, 9H), 1.31 (d, J=6.0Hz, 6H);

Described embodiment is preferred embodiment of the present invention; but the present invention is not limited to above-mentioned embodiment; when not deviating from flesh and blood of the present invention, any apparent improvement that those skilled in the art can make, replacement or modification all belong to protection scope of the present invention.

Claims (8)

1. the synthetic method of a α, β-dehydrogenation-a-amino acid, is characterized in that, comprise the steps: that by the N-alkoxycarbonyl amido acid esters containing beta-hydroxy be starting raw material, be dissolved in organic solvent, and under the activation of SULPHURYL CHLORIDE and DMAP, under organic bases effect, stirring reaction at 10 ~ 30 DEG C, through aftertreatment, obtain N-carbalkoxy-O-alkyl-α, β-unsaturated amino acid, yield 50% to 95%, reaction formula is:
Wherein, R is aryl or alkyl, R 1for hydrogen (H) or methyl (Me), R 2for the tertiary butyl ( tbu), benzyl (Bn) or 9-fluorene methyl, R 3for methyl (Me), ethyl (Et), the tertiary butyl ( tbu), allyl group (ally) or benzyl.
2. the synthetic method of a kind of α, β according to claim 1-dehydrogenation-a-amino acid, is characterized in that, the described N-alkoxycarbonyl amido acid esters concentration in organic solvent containing beta-hydroxy is 0.01 ~ 2mol/L.
3. a kind of α according to claim 1, the synthetic method of β-dehydrogenation-a-amino acid, it is characterized in that, the described N-alkoxycarbonyl amido acid esters containing beta-hydroxy: SULPHURYL CHLORIDE: DMAP: the ratio of the amount of substance of organic bases is 1:1 ~ 4:0.05 ~ 0.6:1 ~ 20.
4. the synthetic method of a kind of α, β according to claim 1-dehydrogenation-a-amino acid, is characterized in that, the described reaction times is 5 minutes to 48 hours.
5. the synthetic method of a kind of α, β according to claim 1 or 3-dehydrogenation-a-amino acid, is characterized in that, described organic bases is triethylamine, Tributylamine, pyridine, 1,8-diazacyclo [5,4,0] hendecene-7, diisopropyl ethyl amine.
6. the synthetic method of a kind of α, β according to claim 1-dehydrogenation-a-amino acid, is characterized in that, described organic solvent is methylene dichloride, ethyl acetate, acetonitrile.
7. a kind of α according to claim 1, the synthetic method of β-dehydrogenation-a-amino acid, it is characterized in that, described aftertreatment is: after reaction mixture reaction terminates, add organic solvent diluting, wash three times, collect organic phase, then with saturated common salt washing, finally anhydrous sodium sulfate drying is used.After rotary evaporation of solvent, obtain thick product.Column chromatography for separation.
8. the synthetic method of a kind of α, β according to claim 7-dehydrogenation-a-amino acid, is characterized in that, described organic solvent is recommended as ethyl acetate, methylene dichloride, ether; Described consumption of organic solvent is every mmole N-carbalkoxy-O-alkoxyamino acid 1 to 50 milliliter.
CN201510278107.7A 2015-05-27 2015-05-27 Alpha,beta-dehydrogenated-alpha-amino acid synthesis method CN105037210A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060678A2 (en) * 2004-12-03 2006-06-08 Bristol-Myers Squibb Company Novel processes for the preparation of cgrp-receptor antagonists and intermediates thereof
WO2013169348A1 (en) * 2012-05-09 2013-11-14 Merck Sharp & Dohme Corp. Process for making cgrp receptor antagonists
CN104168768A (en) * 2012-03-14 2014-11-26 默沙东公司 Process for making cgrp receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060678A2 (en) * 2004-12-03 2006-06-08 Bristol-Myers Squibb Company Novel processes for the preparation of cgrp-receptor antagonists and intermediates thereof
CN104168768A (en) * 2012-03-14 2014-11-26 默沙东公司 Process for making cgrp receptor antagonists
WO2013169348A1 (en) * 2012-05-09 2013-11-14 Merck Sharp & Dohme Corp. Process for making cgrp receptor antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ULRIKE GUNTHER等: ""Polyelectrolytes with Tunable Charge Based on Polydehydroalanine: Synthesis and Solution Properties"", 《MACROMOLECULAR CHEMISTRY AND PHYSICS》 *
程化等: ""脱氢丙氨酸酯、酰胺的合成方法研究"", 《化学研究与应用》 *

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Application publication date: 20151111