CN101875620A - Preparation method of Nalpha-fluorenylmethoxycarbonyl-Ngamma-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,4-diaminobutyric acid - Google Patents
Preparation method of Nalpha-fluorenylmethoxycarbonyl-Ngamma-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,4-diaminobutyric acid Download PDFInfo
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- CN101875620A CN101875620A CN200910050156XA CN200910050156A CN101875620A CN 101875620 A CN101875620 A CN 101875620A CN 200910050156X A CN200910050156X A CN 200910050156XA CN 200910050156 A CN200910050156 A CN 200910050156A CN 101875620 A CN101875620 A CN 101875620A
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Abstract
The invention provides a preparation method of Nalpha-fluorenylmethoxycarbonyl-Ngamma-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,4-diaminobutyric acid, comprising the following steps: (1) dissolving Nalpha-fluorenylmethoxycarbonyl-L-2,4-diaminobutyric acid 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 γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 4-DAB.
Background technology
L-2, the 4-DAB is a requisite mesostate in the body metabolism, is a kind of nonprotein amino acid, and not only the form with free amino acid exists, also extensively be present in occurring in nature, for example polymyxin etc. as many important component parts with peptide of anti-microbial activity.L-2; the 4-DAB still is the key intermediate of tetrahydrobiopterin synthesis pyrimidine; tetrahydropyrimidine can be stablized biomacromolecule and membrane structures such as the hydration layer, protective enzyme, DNA of natural protein, various adverse circumstances such as group's group cell resistance is freezing, arid, high temperature, high salt, radiation.Tetrahydropyrimidine also can be used for preventing skin aging, the stablizer as enzyme, the protective material of microorganism, the chemotherapeutic protection agent of treatment cancer etc.
Since L-2, the multi-function health-care effect of 4-DAB, and this is applied in the chemiluminescent polypeptide field it more and more widely.L-2 during polypeptide is synthetic; the 4-DAB must carry out orthogonally protect could satisfy the synthetic requirement; N α-fluorenes methoxy carbonyl acyl group-N γ-1-(4; 4-dimethyl-2; 6-dioxo cyclohexylene)-3-methyl butyl-L-2; 4-DAB [Fmoc-Dab (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 a kind of N α-fluorenes methoxy carbonyl acyl group-N γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the synthetic technology of 4-DAB.
Summary of the invention
The purpose of this invention is to provide a kind of fast, N α-fluorenes methoxy carbonyl acyl group-N γ-1-(4,4-dimethyl-2,6-dioxo the cyclohexylene)-3-methyl butyl-L-2 of high yield, the preparation method of 4-DAB.
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 γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 4-DAB is characterized in that, may further comprise the steps:
(1) with N α-fluorenes methoxy carbonyl acyl group-L-2, the 4-DAB 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 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 4-DAB 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: 1-1: 6, be preferably 1: 2-1: 4.
The invention provides a kind of preparation N α-fluorenes methoxy carbonyl acyl group-N γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the 4-DAB 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 γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2,4-DAB 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 (50ml) of 4-DAB 5g (13mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 2.97g (13mmol), 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: 1] recrystallization, after the oven dry product 6.4g, productive rate 88%.
Embodiment 2
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the methanol solution (120ml) of 4-DAB 10g (26.5mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 7.14g (31.8mmol), 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: 3] recrystallization, after the oven dry product 13.2g, productive rate 91%.
Embodiment 3
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (200ml) of 4-DAB 20g (53mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 15.5g (69mmol), 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 27.6g, productive rate 95%.
Embodiment 4
In reaction flask, add N α-fluorenes methoxy carbonyl acyl group-L-2; the ethanolic soln (200ml) of 4-DAB 20g (53mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 17.9g (79.5mmol), 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: 4] 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 4-DAB 20g (53mmol), and adding 1-under stirring (4,4-dimethyl-2; 6-dioxo cyclohexylene)-and 3-methyl butanol 35.7g (159mmol), 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: 6] 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 (10)
1. N α-fluorenes methoxy carbonyl acyl group-N γ-1-(4,4-dimethyl-2,6-dioxo cyclohexylene)-3-methyl butyl-L-2, the preparation method of 4-DAB is characterized in that, may further comprise the steps:
(1) with N α-fluorenes methoxy carbonyl acyl group-L-2, the 4-DAB 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 4-DAB 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 4-DAB 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.
9. preparation method according to claim 1 is characterized in that the purification process of described product comprises recrystallization, and described recrystallization method is that employing mixed volume ratio is 1: 1-1: 6 the ethyl acetate and the mixed solvent of sherwood oil carry out recrystallization.
10. preparation method according to claim 9 is characterized in that, the mixed volume ratio of described ethyl acetate and sherwood oil is 1: 2-1: 4.
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| CN200910050156XA CN101875620A (en) | 2009-04-28 | 2009-04-28 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Ngamma-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,4-diaminobutyric acid |
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| CN200910050156XA CN101875620A (en) | 2009-04-28 | 2009-04-28 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Ngamma-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl-L-2,4-diaminobutyric acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892845A (en) * | 2017-02-28 | 2017-06-27 | 四川同晟生物医药有限公司 | A kind of 2,4 diaminobutyric acid derivatives and preparation method thereof |
| CN110305042A (en) * | 2019-07-01 | 2019-10-08 | 吉尔生化（上海）有限公司 | N α-fluorenylmethyloxycarbonyl-N γ-(4,4- dimethyl -2,6- dioxo hexamethylene subunit) ethyl-butyric acid preparation method |
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2009
- 2009-04-28 CN CN200910050156XA patent/CN101875620A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 李文曲等: "末端N-Ivdde保护的氨基酸的合成", 《合成化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892845A (en) * | 2017-02-28 | 2017-06-27 | 四川同晟生物医药有限公司 | A kind of 2,4 diaminobutyric acid derivatives and preparation method thereof |
| CN106892845B (en) * | 2017-02-28 | 2018-10-30 | 四川同晟生物医药有限公司 | A kind of 2,4- diaminobutyric acid derivatives and preparation method thereof |
| CN110305042A (en) * | 2019-07-01 | 2019-10-08 | 吉尔生化（上海）有限公司 | N α-fluorenylmethyloxycarbonyl-N γ-(4,4- dimethyl -2,6- dioxo hexamethylene subunit) ethyl-butyric acid preparation method |
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Application publication date: 20101103 |