CN101575304A - Method for preparing Nalpha-Fmoc-Nepsilon-1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutyl-L-ornithine - Google Patents
Method for preparing Nalpha-Fmoc-Nepsilon-1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutyl-L-ornithine Download PDFInfo
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- CN101575304A CN101575304A CNA2009100490264A CN200910049026A CN101575304A CN 101575304 A CN101575304 A CN 101575304A CN A2009100490264 A CNA2009100490264 A CN A2009100490264A CN 200910049026 A CN200910049026 A CN 200910049026A CN 101575304 A CN101575304 A CN 101575304A
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Abstract
The invention belongs to the field of polypeptide chemistry, and relates to a protection method for amino acid, in particular to a protection method of ornithine. The invention provides a method for preparing Nalpha-Fmoc-Nepsilon-1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutyl-L-ornithine, which comprises the following steps: adding 1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutanol into an ethanol solution of Nalpha-Fmoc-L-ornithine, and reacting the two materials under a proper condition; after the reaction, adding proper acid to adjust the pH value; and separating and purifying the expected product according to a conventional method. The method has the advantages of fastness, high yield, and simple separation and purification, and the used solvent is environment-friendly.
Description
Technical field
The present invention relates to the preparation method of a kind of N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine, belong to the chemiluminescent polypeptide field.
Background technology
L-ornithine (L-ornithine, H
2NCH
2CH
2CH
2CH (NH
2) COOH), be that a kind of nonprotein is formed amino acid, be present in the germ resistance peptide of tyrocidine, Gramicidin S etc., from the corydalis root of remote mountains, found δ-N-acetylornithice in addition.The L-ornithine in vivo with arginine, L-glutamic acid, proline(Pro) co-conversion mutually, can carry out transamination with alpha-ketoacid, oxoethanoic acid, decarboxylation under the effect of ornithine deshydroxy enzyme and generate amine (butanediamine), butanediamine can further be blended into polyamines.The L-ornithine is a requisite mesostate in the body metabolism, and it mainly participates in as uric acid circulation, has vital role for the discharge of ammonia-state nitrogen in the body.
The multi-functional health-care effect of ornithine is applied in the chemiluminescent polypeptide field it more and more widely.Ornithine during polypeptide is synthetic must carry out orthogonally protect and could satisfy the synthetic requirement; N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4; 4-dimethyl-2; 6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine [Fmoc-Orn (ivDde)-OH] is highly stable in trifluoroacetic acid (TFA) and piperidines-dimethyl formamide environment; in dimethyl formamide, very easily removed again simultaneously, so in the liquid phase of grafting, cyclisation peptide is synthetic, great using value is arranged by 2% hydrazine solution.Studies show that, with 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol as the amino acid of protecting group at spider venom [J.Am.Chem.Soc., 1994,116:7415-7416; Tetra.Lett., 1996,37:2625-2628] and trypanosome bar toxin synthetic in good application is arranged.The invention provides the preparation method of a kind of N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine.
Summary of the invention
The purpose of this invention is to provide a kind of fast, the preparation method of N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo the cyclohexylene)-3-methyl butyl-L-ornithine of high yield.
The technical problem that will solve required for the present invention can be achieved through the following technical solutions:
The preparation method of a kind of N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine is characterized in that, may further comprise the steps:
(1) N α-fluorenes methoxy carbonyl acyl group-L-ornithine (Fmoc-Orn-OH) is dissolved in the suitable organic solvent, and reacts under suitable condition with 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol;
(2) after reaction finishes, add suitable acid for adjusting pH value;
(3) separate desired product and purifying subsequently according to a conventional method:
Described conventional purification procedures comprises:
A, adding organic solvent extraction;
B, in the organic phase of extraction gained, add the washing of citric acid, saturated aqueous sodium chloride successively, add the siccative drying then, concentrate and make product;
C, product is carried out recrystallization.
The mol ratio of described N α-fluorenes methoxy carbonyl acyl group-L-ornithine and 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol is 1: 1-1: 3, be preferably 1: 1-1: 1.3.
Suitable organic solvent described in preparation method's step of the present invention (1) includes a kind of in ethanol, methyl alcohol, ethyl acetate, tetrahydrofuran (THF) and their analogue or their mixing, and described suitable condition is at 10 ℃ of-40 ℃ of following stirring reactions.
Suitable acid described in preparation method's step of the present invention (2) comprises a kind of in mineral acid, citric acid, trifluoroacetic acid, acetate and their analogue or their mixing; Described pH value scope is 1-6, is preferably 1-3.
Organic solvent described in preparation method's step a of the present invention comprises ethyl acetate or methylene dichloride etc.
Siccative described in preparation method's step b of the present invention comprises anhydrous sodium sulphate, anhydrous magnesium sulfate or Calcium Chloride Powder Anhydrous etc.
Recrystallization method described in preparation method's step c of the present invention is to adopt the mixed solvent of ethyl acetate and sherwood oil to carry out recrystallization.
The mixed volume ratio of described ethyl acetate and sherwood oil is 1: 3-1: 6.
The invention provides a kind of preparation N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo one cyclohexylene)-3-methyl butyl-L-ornithine fast, the novel method of high yield.Implement method of the present invention by adopting the parent material that obtains easily.And the N α that this method prepares-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine output height, separation and purifying are simple, and use environment amenable solvent.
Embodiment
In order to make technique means of the present invention, creation characteristic, to reach purpose and effect is easy to understand,, further set forth the present invention, but embodiments of the present invention are not limited thereto below in conjunction with specific embodiment.
Embodiment 1
The ethanolic soln (50ml) that in reaction flask, adds N α-fluorenes methoxy carbonyl acyl group-L-ornithine 4g (11mmol); stir and add 1-(4 down; 4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol 2.45g (11mmol), 10 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with citric acid is 1, adds ethyl acetate (3 * 100ml) extractions then.Merge organic phase, use saturated aqueous solution (50ml) washing of 10% aqueous citric acid solution (50ml) and sodium-chlor successively, anhydrous sodium sulphate (10g) drying; Revolve and obtain faint yellow oily thing after inspissation contracts, add mixed solvent [V (ethyl acetate)/V (sherwood oil)=1: 3] recrystallization, after the oven dry product 5.3g, productive rate 85%.
Embodiment 2
The methanol solution (100ml) that in reaction flask, adds N α-fluorenes methoxy carbonyl acyl group-L-ornithine 8g (22mmol); stir and add 1-(4 down; 4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol 5.88g (26mmol), 20 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with hydrochloric acid is 2, adds ethyl acetate (3 * 150ml) extractions then.Merge organic phase, use saturated aqueous solution (50ml) washing of 10% aqueous citric acid solution (80ml) and sodium-chlor successively, anhydrous magnesium sulfate (10g) drying; Revolve and obtain faint yellow oily thing after inspissation contracts, add mixed solvent [V (ethyl acetate)/V (sherwood oil)=1: 4] recrystallization, after the oven dry product 11.3g, productive rate 90%.
Embodiment 3
The ethanolic soln (120ml) that in reaction flask, adds N α-fluorenes methoxy carbonyl acyl group-L-ornithine 10g (27.3mmol); stir and add 1-(4 down; 4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol 7.87g (35.5mmol), 40 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with trifluoroacetic acid is 3, adds methylene dichloride (3 * 150ml) extractions then.Merge organic phase, use saturated aqueous solution (60ml) washing of 10% aqueous citric acid solution (80ml) and sodium-chlor successively, Calcium Chloride Powder Anhydrous (10g) drying; Revolve and obtain faint yellow oily thing after inspissation contracts, add mixed solvent [V (ethyl acetate)/V (sherwood oil)=1: 5] recrystallization, after the oven dry product 14.4g, productive rate 92%.
Embodiment 4
The ethanolic soln (130ml) that in reaction flask, adds N α-fluorenes methoxy carbonyl acyl group-L-ornithine 10g (27mmol); stir and add 1-(4 down; 4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol 12.11g (54mmol), 35 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with dilute sulphuric acid is 3, adds methylene dichloride (3 * 150ml) extractions then.Merge organic phase, use saturated aqueous solution (60ml) washing of 10% aqueous citric acid solution (80ml) and sodium-chlor successively, anhydrous magnesium sulfate (10g) drying; Revolve and obtain faint yellow oily thing after inspissation contracts, add mixed solvent [V (ethyl acetate)/V (sherwood oil)=1: 3] recrystallization, after the oven dry product 14.24g, productive rate 91%.
Embodiment 5
The ethanolic soln (135ml) that in reaction flask, adds N α-fluorenes methoxy carbonyl acyl group-L-ornithine 10g (27mmol); stir and add 1-(4 down; 4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol 18.17g (81mmol), 40 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with acetate is 4, adds methylene dichloride (3 * 150ml) extractions then.Merge organic phase, use saturated aqueous solution (60ml) washing of 10% aqueous citric acid solution (80ml) and sodium-chlor successively, anhydrous magnesium sulfate (10g) drying; Revolve and obtain faint yellow oily thing after inspissation contracts, add mixed solvent [V (ethyl acetate)/V (sherwood oil)=1: 3] recrystallization, after the oven dry product 13.77g, productive rate 88%.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (8)
1, the preparation method of a kind of N α-fluorenes methoxy carbonyl acyl group-N ε-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-ornithine is characterized in that, may further comprise the steps:
(1) N α-fluorenes methoxy carbonyl acyl group-L-ornithine is dissolved in the suitable organic solvent, and reacts under suitable condition with 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol;
(2) after reaction finishes, add suitable acid for adjusting pH value;
(3) separate desired product and purifying subsequently according to a conventional method.
2, preparation method according to claim 1 is characterized in that, the mol ratio of described N α-fluorenes methoxy carbonyl acyl group-L-ornithine and 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol is 1: 1-1: 3.
3, preparation method according to claim 2 is characterized in that, the mol ratio of described N α-fluorenes methoxy carbonyl acyl group-L-ornithine and 1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butanol is 1: 1-1: 1.3.
4, preparation method according to claim 1 is characterized in that, the suitable organic solvent described in the step (1) includes a kind of in ethanol, methyl alcohol, ethyl acetate, tetrahydrofuran (THF) and their analogue or their mixing.
5, preparation method according to claim 1 is characterized in that, suitable condition described in the step (1) is at 10 ℃ of-40 ℃ of following stirring reactions.
6, preparation method according to claim 1 is characterized in that, the suitable acid described in the step (2) comprises a kind of in mineral acid, citric acid, trifluoroacetic acid, acetate and their analogue or their mixing.
7, preparation method according to claim 1 is characterized in that, the pH value scope described in the step (2) is 1-6.
8, preparation method according to claim 7 is characterized in that, described pH value scope is 1-3.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100490264A CN101575304A (en) | 2009-04-09 | 2009-04-09 | Method for preparing Nalpha-Fmoc-Nepsilon-1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutyl-L-ornithine |
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| CNA2009100490264A CN101575304A (en) | 2009-04-09 | 2009-04-09 | Method for preparing Nalpha-Fmoc-Nepsilon-1-(4,4-dimethyl-2,6-dioxo-cycloethylene)-3-methylbutyl-L-ornithine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033033A (en) * | 2016-10-14 | 2017-08-11 | 上海吉尔多肽有限公司 | The synthetic method of hydroxytyrosine between a kind of N α fluorenylmethyloxycarbonyls |
| CN111454180A (en) * | 2020-04-10 | 2020-07-28 | 大连阿拉宁生物技术有限公司 | Somalutide side chain intermediate and preparation method thereof |
-
2009
- 2009-04-09 CN CNA2009100490264A patent/CN101575304A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033033A (en) * | 2016-10-14 | 2017-08-11 | 上海吉尔多肽有限公司 | The synthetic method of hydroxytyrosine between a kind of N α fluorenylmethyloxycarbonyls |
| CN111454180A (en) * | 2020-04-10 | 2020-07-28 | 大连阿拉宁生物技术有限公司 | Somalutide side chain intermediate and preparation method thereof |
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