CN101875621A - Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate - Google Patents
Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate Download PDFInfo
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- CN101875621A CN101875621A CN2009100501574A CN200910050157A CN101875621A CN 101875621 A CN101875621 A CN 101875621A CN 2009100501574 A CN2009100501574 A CN 2009100501574A CN 200910050157 A CN200910050157 A CN 200910050157A CN 101875621 A CN101875621 A CN 101875621A
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Abstract
The invention provides a preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate, comprising the following steps: (1) dissolving Nalpha-fluorenylmethoxycarbonyl-L-2,3-diaminopropionate into an appropriate organic solvent to react with 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutanol under appropriate conditions; (2) after reaction, adding appropriate acid to adjust the pH value; and (3) later separating out the expected products by the conventional method and purifying the products. The method has the advantages of rapidness, high yield and simple separation and purification, and the used solvent is environmentally friendly.
Description
Technical field
The present invention relates to a kind of N α-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 3-diaminopropionic acid.
Background technology
L-2,3-diaminopropionic acid are requisite mesostates in the body metabolism.It is a kind of nonprotein amino acid, and not only the form with free amino acid exists, and also the important component part as peptide extensively is present in occurring in nature.In these peptides, many have antitumor and anti-microbial activity, as Viothenate (viomycin), capromycin (capreomycin), tuberactinomycin (tuberactinomycin) etc.L-2,3-diaminopropionic acid or derivatives thereof also are used as crucial structural unit and make up some and be proved to be effective peptides, as enzyme inhibitors, and metal chelator, and GPIIb/IIIa antagonist.Because L-2, the 3-diaminopropionic acid has multi-functional health-care effect, and this is applied in the chemiluminescent polypeptide field it more and more widely.In polypeptide is synthetic, L-2, the 3-diaminopropionic acid must carry out orthogonally protect could satisfy the synthetic requirement.Also there are some researches show, 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.Because N α-fluorenes methoxy carbonyl acyl group-N β-1-(4; 4-dimethyl-2; 6-dioxo cyclohexylene)-3-methyl butyl-L-2; 3-diaminopropionic acid [Fmoc-Dap (ivDde)-OH] is highly stable in trifluoroacetic acid (TFA) and piperidines-dimethyl formamide environment; in dimethyl formamide, very easily removed again simultaneously by 2% hydrazine solution; so the L-2 of synthetic protection, the 3-diaminopropionic acid has very large meaning, in the liquid phase of grafting, cyclisation peptide is synthetic great using value is arranged.The invention provides a kind of N α-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the synthetic technology of 3-diaminopropionic acid.
Summary of the invention
The purpose of this invention is to provide a kind of fast, N α-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo the cyclohexylene)-3-methyl butyl-L-2 of high yield, the preparation method of 3-diaminopropionic acid.
The technical problem that will solve required for the present invention can be achieved through the following technical solutions:
A kind of N α-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 3-diaminopropionic acid is characterized in that, may further comprise the steps:
(1) with N α-fluorenes methoxy carbonyl acyl group-L-2, the 3-diaminopropionic acid is dissolved in the suitable organic solvent,
And react 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 10% aqueous citric acid solution, saturated aqueous sodium chloride successively, add the siccative drying then, concentrate and make product;
C, product is carried out recrystallization.
Described N α-fluorenes methoxy carbonyl acyl group-L-2, the mol ratio of 3-diaminopropionic acid 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, and the mixed volume ratio of described ethyl acetate and sherwood oil is 1: 3.
The invention provides a kind of preparation N α-fluorenes methoxy carbonyl acyl group-N β-1-(4; 4-dimethyl-2; 6-dioxo cyclohexylene)-3-methyl butyl-L-2; the novel method of 3-diaminopropionic acid; adopt single stage method to implement the present invention by the parent material that obtains easily, be a kind of fast, the novel method of high yield.And, the N α that this method prepares-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2,3-diaminopropionic acid 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
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (40ml) of 3-diaminopropionic acid 3g (9mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 2g (9mmol), 10 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with citric acid is 1, adds ethyl acetate (3 * 80ml) 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 4.26g, productive rate 87%.
Embodiment 2
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the methanol solution (80ml) of 3-diaminopropionic acid 6g (18mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 4.9g (22mmol), 20 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with hydrochloric acid is 2, adds ethyl acetate (3 * 120ml) 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: 3] recrystallization, after the oven dry product 8.7g, productive rate 89%.
Embodiment 3
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (200ml) of 3-diaminopropionic acid 15g (46mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 13.4g (60mmol), 40 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with trifluoroacetic acid is 3, adds ethyl acetate (3 * 200ml) extractions then.Merge organic phase, use saturated aqueous solution (80ml) washing of 10% aqueous citric acid solution (100ml) and sodium-chlor successively, anhydrous sodium sulphate (20g) 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 22.8g, productive rate 93%.
Embodiment 4
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (200ml) of 3-diaminopropionic acid 15g (46mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 17.9g (92mmol), 35 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with dilute sulphuric acid is 3, adds methylene dichloride (3 * 250ml) extractions then.Merge organic phase, use saturated aqueous solution (80ml) washing of 10% aqueous citric acid solution (100ml) and sodium-chlor successively, anhydrous magnesium sulfate (20g) 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 26.1g, productive rate 90%.
Embodiment 5
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (250ml) of 3-diaminopropionic acid 15g (46mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 30.82g (138mmol), 40 ℃ of reactions (TLC detection) down.Reaction finishes, and transferring pH with acetate is 4, adds methylene dichloride (3 * 300ml) extractions then.Merge organic phase, use saturated aqueous solution (80ml) washing of 10% aqueous citric acid solution (100ml) and sodium-chlor successively, anhydrous magnesium sulfate (25g) 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 25.0g, productive rate 86%.
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. N α-fluorenes methoxy carbonyl acyl group-N β-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 3-diaminopropionic acid is characterized in that, may further comprise the steps:
(1) with N α-fluorenes methoxy carbonyl acyl group-L-2, the 3-diaminopropionic acid 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, described N α-fluorenes methoxy carbonyl acyl group-L-2, and the mol ratio of 3-diaminopropionic acid 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, described N α-fluorenes methoxy carbonyl acyl group-L-2, and the mol ratio of 3-diaminopropionic acid 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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| CN2009100501574A CN101875621A (en) | 2009-04-28 | 2009-04-28 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate |
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| CN2009100501574A CN101875621A (en) | 2009-04-28 | 2009-04-28 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate |
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| CN101875621A true CN101875621A (en) | 2010-11-03 |
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| CN2009100501574A Pending CN101875621A (en) | 2009-04-28 | 2009-04-28 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nbeta-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,3-diaminopropionate |
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- 2009-04-28 CN CN2009100501574A patent/CN101875621A/en active Pending
Non-Patent Citations (1)
| Title |
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| 李文曲等: "末端N-Ivdde保护的氨基酸的合成", 《合成化学》 * |
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Application publication date: 20101103 |