CN109180533A - A kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester - Google Patents
A kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester Download PDFInfo
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- CN109180533A CN109180533A CN201811119957.2A CN201811119957A CN109180533A CN 109180533 A CN109180533 A CN 109180533A CN 201811119957 A CN201811119957 A CN 201811119957A CN 109180533 A CN109180533 A CN 109180533A
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- tert
- asp
- fluorenylmethyloxycarbonyl
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- butyl ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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Abstract
The invention discloses a kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester preparation method, (a) tert-butyl acetate is added into reaction vessel, and catalyst is added dropwise, D-ASP is added, it is reacted in 20-50 DEG C, concentration obtains D- asparagus fern door propylhomoserin di tert butyl carbonate；(b) D-ASP di tert butyl carbonate is added in copper-bath, adjusts pH value to 4-8, obtains D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution；(c) organic solvent and disodium ethylene diamine tetraacetate are sequentially added into D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution, it stirs evenly, fluorenes methoxy carbonyl acyl succinimide is added into solution system again, adjusts pH value to 3-5, stratification, extraction, petroleum ether is added in dry organic layer, filtering, organic layer, stirred crystallization obtains N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester.Preparation method of the invention avoids racemization in process of production, improves the optical purity of product.
Description
Technical field
The invention belongs to technical field of medical chemistry, and in particular to a kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4-
The tert-butyl ester.
Background technique
During organic chemical reactions, same substance can be prepared using different preparation methods, but different
The yield of the resulting final physical product of preparation method exist different, while can be produced in the reaction process of different preparation methods
Raw different impurity, so as to cause it is subsequent it is final during dedoping step become complicated, increase the cost of substance reaction.It closes
In N-9- fluorenylmethyloxycarbonyl-D-Asp -4- tert-butyl ester traditional preparation methods, original preparation N-9- fluorenylmethyloxycarbonyl -
The method and process step of the substance of the D-Asp -4- tert-butyl ester is more, includes mainly five steps, the first step is D- asparagus fern ammonia
Acid reacts in the mixed solution of phosphorus trichloride and tetrahydrofuran, and the water for sloughing a molecule obtains D-Asp inner-acid anhydride；The
Two steps are that gained D-Asp inner-acid anhydride and ethanol synthesis obtain ester in first step reaction；Third step is the product in second step
Transesterification reaction, which is carried out, with perchloric acid and tert-butyl acetate obtains D-Asp tert-butyl ester ethyl ester；4th step is by institute in third step
The substance of generation reacts under aqueous slkali environment obtains product；5th step is by product obtained in four-step reaction and Fmoc-
Osu reaction, finally obtains N-9- fluorenylmethyloxycarbonyl-D-Asp -4- tert-butyl ester；The N-9- prepared using this kind of preparation method
Fluorenylmethyloxycarbonyl-D-Asp -4- the tert-butyl ester, required preparation synthetic route is longer, while according to reaction in practice
It finds in the process, under this kind of synthesis preparation method, on the one hand because preparation step is more, causes to be also easy to produce during the reaction other
Impurity, so that subsequent purification difficulty is increased, on the other hand because of the receipts for the product being finally synthetically prepared under this kind of preparation method
Rate is low, and preparation cost is high, while using this kind of preparation method, is easy to cause final obtained product to generate racemization, leads to light
It is not high to learn purity.
Summary of the invention
It is an object of the invention to: above-mentioned deficiency in the prior art is solved, provides a kind of N-9- fluorenylmethyloxycarbonyl-D- days
The preparation method of the L-aminobutanedioic acid -4- tert-butyl ester, using this preparation method on the one hand can reduce reaction the step of so that operation more
To be simple, while it can also shorten the production cycle of product；On the other hand the receipts of product be can be improved using this kind of preparation method
Rate can be avoided product racemization, generates N- (the 9-fluorenylmethyloxycarbonyl)-O- tert-butyl ester-ASPARTIC ACID, improves the light of this product
Learn purity.
To achieve the goals above, a kind of the technical solution adopted by the present invention are as follows: N-9- fluorenylmethyloxycarbonyl-D- asparagine
The preparation method of the acid -4- tert-butyl ester, it is characterised in that: reacted by following reaction equations:
Include the following steps,
(a) tert-butyl acetate is added into reaction vessel, then catalyst is added dropwise into reaction vessel, adds D- lucid asparagus
Propylhomoserin is reacted in 20-50 DEG C, and after reaction, concentration obtains D- asparagus fern door propylhomoserin di tert butyl carbonate；
(b) the D-ASP di tert butyl carbonate obtained in above-mentioned steps (a) is added in copper-bath, adjusts pH
Value stirs evenly to 4-8, obtains D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution；
(c) it is sequentially added into the D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution that above-mentioned steps (b) obtain organic molten
Agent and disodium ethylene diamine tetraacetate, stir evenly, then fluorenes methoxy carbonyl acyl succinimide is added into solution system, adjust pH value
To 3-5, sufficiently after reaction, stratification is extracted, dry organic layer, filtering, and petroleum ether is added in organic layer, and stirred crystallization obtains
N-9- fluorenylmethyloxycarbonyl-D-ASP -4- the tert-butyl ester, then it is purified with ethyl acetate and petroleum ether, obtain height
The finished product of purity.
Further, in the step (a), the ratio between the amount of substance of the tert-butyl acetate and the D-ASP
For 6-8:1.
Further, in the step (b), the concentration of the copper-bath is 5-10mol/L.
Further, in the step (b), reaction temperature is 30-80 DEG C.
Further, in the step (a), it is mass fraction 20-40%'s that the lye, which neutralizes used lye,
The aqueous solution of NaOH.
Further, in the step (c), the D- asparagus fern door propylhomoserin di tert butyl carbonate mantoquita and the ethylenediamine tetrem
The ratio between amount of substance of acid disodium is 1:1-2.
Further, the organic solvent is the mixture of one or both of ethyl acetate, tetrahydrofuran.
Further, in the step (a), the concentration includes that distilled water is added into the reaction system,
Add NaHCO3Solid stirs evenly, and adjusts pH value to 7-8 with the NaOH aqueous solution of mass fraction 20-40%, stands and divide
Layer washs organic layer, anhydrous Na2SO4Dry organic layer, then negative pressure concentration of organic layers.
Further, in the step (a), the catalyst is inorganic acid.
Further, the inorganic acid is the mixture of one or both of perchloric acid, sulfuric acid.
By adopting the above-described technical solution, the beneficial effects of the present invention are:
Preparation method preparation process of the invention is simple, and used acid binding agent is Carbon Dioxide during the reaction
Sodium and NaOH, this two kinds of cost of material are low, easily purchase；One acetoacetic ester of solvent employed in next preparation process of the invention,
Tert-butyl acetate, petroleum ether etc., have the characteristics that small toxicity, convenient sources, it is cheap, be easy recycling, reduce and be prepared into
This, can widely apply in industrial processes；
Preparation method of the invention avoids racemization in process of production, improves the optical purity of product.
Specific embodiment
The embodiment of the present invention is prepared according to following reaction equations:
Embodiment 1:
Tert-butyl acetate 90g is added in reaction flask, is added dropwise to H2SO45g is being added dropwise to HClO4(perchloric acid) 12g, adds
Enter D-ASP 13.3g to react 12 hours, TLC (thin-layered chromatography) detection to system is reacted substantially without D-ASP
When, reaction is completed, and D- asparagus fern door propylhomoserin di tert butyl carbonate is obtained；
Add water 90g into reaction system, is slowly added to NaHCO3Then 38g is stirred reaction system, then use
30%NaOH adjusts the PH to 8 of reaction system, is then allowed to stand layering, separation and Extraction organic layer, to organic layer NaCl aqueous solution
Washing 2 times, adds the anhydrous Na of 30g2SO4Dry organic layer, after 1 hour dry, filtering, negative pressure is concentrated to give two uncle of D-Asp
Butyl ester 15g；
Add water 110g in a clean reaction flask, adds CuSO4·5H2The temperature of solution system is risen to 45 DEG C by O 15g,
Then D-Asp di tert butyl carbonate 15g is added, adds the NaOH 15g of 5mol/L, reacts 2.5 hours, obtains containing water layer
D-Asp -4- tert-butyl ester mantoquita；
Add Na into the water-bearing layer D-Asp -4- tert-butyl ester mantoquita that above-mentioned steps obtain2CO320g adds acetic acid
Ethyl ester 200g, disodium ethylene diamine tetraacetate 15g, fluorenes methoxy carbonyl acyl succinimide 25g, to the end of reacting, stratification, separation
Organic layer is obtained, has the pH of layer to 3 with HCl adjusting, is washed organic layer 4 times with NaCl aqueous solution, add anhydrous Na2SO420g is dry
1 hour, filtering took filtrate (organic layer), is then concentrated into 50ml to filtrate progress negative pressure and obtains N-9- fluorenylmethyloxycarbonyl-D- days
L-aminobutanedioic acid -4- the tert-butyl ester, is added petroleum ether (60-90 degree) 60g, and stirred crystallization filters to obtain 33g N-9- fluorenylmethyloxycarbonyl-D-
The thick wet product of the asparatate -4- tert-butyl ester；The thick wet product of 33g is added in the ethyl acetate of 50g and is dissolved, while in the solution system
Add 60g petroleum ether, be slowly stirred crystallization, filters to obtain N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester wet product 30g, so
It is dry to its row afterwards, obtain 28.7g dry product.
In the present embodiment, the total recovery 70% of product, the appearance of obtained product are off-white powder；Product is pure
Degree: 99.86%, maximum contaminant 0.045% (uses HPLC area normalization method)；Mp:146.1-147.1 DEG C of fusing point；Moisture content (K,
F): 0.3%；Specific rotation [α] 20D:-25.5 (c=1.0, DMF (dimethylformamide))；Optical purity: 99.97%.
Embodiment 2:
Tert-butyl acetate 180g is added in reaction flask, is added dropwise to H2SO410g is being added dropwise to HClO4(perchloric acid) 25g,
D-ASP 26.6g is added to react 15 hours, TLC (thin-layered chromatography) detection to system is reacted substantially without D- asparagine
When sour, reaction is completed, and obtains D- asparagus fern door propylhomoserin di tert butyl carbonate；
Add water 200g into reaction system, is slowly added to NaHCO3Then 80g is stirred reaction system, then use
30%NaOH adjusts the PH to 7 of reaction system, is then allowed to stand layering, separation and Extraction organic layer, to organic layer NaCl aqueous solution
Washing 2 times, adds the anhydrous Na of 60g2SO4Dry organic layer, after 1 hour dry, filtering, negative pressure is concentrated to give two uncle of D-Asp
Butyl ester 31g；
Add water 220g in a clean reaction flask, adds CuSO4·5H2The temperature of solution system is risen to 60 DEG C by O 30g,
Then D-Asp di tert butyl carbonate 31g is added, adds the NaOH 30g of 5mol/L, hour after reaction 3, obtains containing water layer
D-Asp -4- tert-butyl ester mantoquita；
Add Na into the water-bearing layer D-Asp -4- tert-butyl ester mantoquita that above-mentioned steps obtain2CO340g adds acetic acid
Ethyl ester 400g, disodium ethylene diamine tetraacetate 30g, fluorenes methoxy carbonyl acyl succinimide 50g, to the end of reacting, stratification, separation
Organic layer is obtained, has the pH of layer to 3 with HCl adjusting, is washed organic layer 4 times with NaCl aqueous solution, add anhydrous Na2SO440g is dry
1 hour, filtering took filtrate (organic layer), is then concentrated into 100ml to filtrate progress negative pressure and obtains N-9- fluorenylmethyloxycarbonyl-D-
Asparatate -4- the tert-butyl ester, is added petroleum ether (60-90 degree) 150g, and stirred crystallization filters to obtain 65g N-9- fluorenes methoxy carbonyl
Base-thick the wet product of the D-ASP -4- tert-butyl ester；The thick wet product of 65g is added in the ethyl acetate of 100g and is dissolved, while the solution
In system plus 120g petroleum ether, be slowly stirred crystallization, filter N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester is wet
Then product 61g is dried N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester, obtains 59.5g dry product.
In the present embodiment, the total recovery 72.3% of product, the appearance of obtained product are off-white powder；Product is pure
Degree: 99.77%, maximum contaminant 0.032% (uses HPLC area normalization method)；Mp:146.8-147.3 DEG C of fusing point；Moisture content (K,
F): 0.25%；Specific rotation [α] 20D:-26 (c=1.0, DMF (dimethylformamide))；Optical purity: 99.93%.
Embodiment 3:
Tert-butyl acetate 90g is added in reaction flask, is added dropwise to H2SO45g is being added dropwise to HClO4(perchloric acid) 12g, adds
Enter D-ASP 14g to react 15 hours, TLC (thin-layered chromatography) detection to system is reacted substantially without D-ASP
When, after the reaction was completed, obtain D- asparagus fern door propylhomoserin di tert butyl carbonate；
Add water 100g into reaction system, is slowly added to NaHCO3Then 40g is stirred reaction system, then use
30%NaOH adjusts the PH to 7 of reaction system, is then allowed to stand layering, separation and Extraction organic layer, to organic layer NaCl aqueous solution
Washing 2 times, adds the anhydrous Na of 40g2SO4Dry organic layer, after 2 hours dry, filtering, negative pressure is concentrated to give two uncle of D-Asp
Butyl ester 15g；
Add water 120g in a clean reaction flask, adds CuSO4·5H2The temperature of solution system is risen to 80 DEG C by O 15g,
Then D-Asp di tert butyl carbonate 16g is added, adds the NaOH 16g of 5mol/L, reacts 3 hours, obtains the D- containing water layer
Aspartic acid -4- the tert-butyl ester；
Add Na into the water-bearing layer D-Asp -4- tert-butyl ester that above-mentioned steps obtain2CO330g adds ethyl acetate
210g, disodium ethylene diamine tetraacetate 18g, fluorenes methoxy carbonyl acyl succinimide 25g, to the end of reacting, stratification is isolated
Organic layer adjusts the pH to 3 of organic layer with HCl, is washed organic layer 4 times with NaCl aqueous solution, add anhydrous Na2SO430g dry 2
Hour, filtering takes filtrate (organic layer), then carries out negative pressure to filtrate and is concentrated into 50ml, obtains N-9- fluorenylmethyloxycarbonyl-D- days
L-aminobutanedioic acid -4- the tert-butyl ester, is added petroleum ether (60-90 degree) 70g, and stirred crystallization filters to obtain 35g N-9- fluorenylmethyloxycarbonyl-D-
The thick wet product of the asparatate -4- tert-butyl ester；The thick wet product of 35g is added in the ethyl acetate of 55g and is dissolved, while to the solution system
In plus 60g petroleum ether, be slowly stirred crystallization, filter to obtain N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester wet product 31g,
Then it is dried, obtains 29.4g dry product.
In the present embodiment, the total recovery 71.5% of product, the appearance of obtained product are off-white powder；Product is pure
Degree: 99.90%, maximum contaminant 0.04% (uses HPLC area normalization method)；Mp:153.5-153.9 DEG C of fusing point；Moisture content (K, F):
0.23%；Specific rotation [α] 20D:-24.7 (c=1.0, DMF (dimethylformamide))；Optical purity: 99.95%.
The optical purity that the preparation method of above-described embodiment 1-3 obtains product is high, and optical purity is greater than 99.9%, and produces
The total recovery of product is greater than 70%.Preparation method through the invention prepares N-9- fluorenylmethyloxycarbonyl-tertiary fourth of D-ASP -4-
Ester, preparation process is simple, the small toxicities such as used reactant, solvent, cheap, easy recycling.
Claims (9)
1. a kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester preparation method, it is characterised in that: by following anti-
Formula is answered to react:
Include the following steps,
(a) tert-butyl acetate is added into reaction vessel, then catalyst is added dropwise into reaction vessel, adds D- asparagine
Acid is reacted in 20-50 DEG C, and after reaction, concentration obtains D- asparagus fern door propylhomoserin di tert butyl carbonate；
(b) the D-ASP di tert butyl carbonate obtained in above-mentioned steps (a) is added in copper-bath, adjust pH value to
4-8 is stirred evenly, and obtains D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution；
(c) sequentially added into the D- asparagus fern door propylhomoserin di tert butyl carbonate copper salt solution that above-mentioned steps (b) obtain organic solvent and
Disodium ethylene diamine tetraacetate stirs evenly, then fluorenes methoxy carbonyl acyl succinimide is added into solution system, adjusts pH value to 3-
5, sufficiently after reaction, stratification is extracted, dry organic layer, filtering, and petroleum ether, stirred crystallization, ethyl acetate is added in organic layer
And petroleum ether, obtain N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester.
2. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (a), the ratio between amount of substance of the tert-butyl acetate and the D-ASP is 6-8:1.
3. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (b), the concentration of the copper-bath is 5-10mol/L.
4. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (b), reaction temperature is 30-80 DEG C.
5. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (c), the object of D- asparagus fern door the propylhomoserin di tert butyl carbonate mantoquita and the disodium ethylene diamine tetraacetate
The ratio between amount of matter is 1:1-2.
6. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (c), the organic solvent is the mixture of one or both of ethyl acetate, tetrahydrofuran.
7. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (a), the concentration includes that distilled water is added into the reaction system, adds
NaHCO3Solid stirs evenly, and adjusts pH value to 7-8, stratification, washing with the NaOH aqueous solution of mass fraction 20-40%
Organic layer, anhydrous Na2SO4Dry organic layer, then negative pressure concentration of organic layers.
8. N-9- fluorenylmethyloxycarbonyl according to claim 1-D-ASP-4- tert-butyl ester preparation method, special
Sign is: in the step (a), the catalyst is inorganic acid.
9. N-9- fluorenylmethyloxycarbonyl according to claim 8-D-ASP-4- tert-butyl ester preparation method, special
Sign is: the inorganic acid is the mixture of one or both of perchloric acid, sulfuric acid.
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Cited By (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113896657A (en) * | 2021-11-16 | 2022-01-07 | 山东盛安贝新能源有限公司南京分公司 | Synthesis method and purification method of somaglutide protected amino acid |
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