CN114990175B - Synthesis method of fucose derivatives - Google Patents
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Abstract
The invention provides a synthetic method of a fucose derivative medical intermediate GDP-FAm, which comprises the following steps: carrying out enzymatic reaction by taking 6-amino-alpha-L-galactopyranose as a substrate to obtain GDP-FAm; the synthesis method also comprises the step of obtaining the amino-substituted fucose through a mitsunobu reaction and hydrazinolysis. The synthesis method provided by the invention reduces the use of azide reagents, reduces the use of heavy metals and hydrogenation reaction, and greatly improves the safety; the synthesis method of the invention reduces the synthesis steps and the comprehensive yield can reach 56%.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of a fucose derivative.
Background
Fucose (fucose) is a kind of six-carbon sugar, also called 6-deoxy-L-galactopyranose, and most of fucose existing in nature is L-fucose. GDP-FAm (guanosine-5 '-diphosphate, P' - (6-amino-alpha-L-galactopyranose) ester) is a fucose derivative medical intermediate.
The currently reported synthesis route of GDP-FAm in the literature is generally a 6-step reaction, and the synthesis route is as follows:
there are several drawbacks and disadvantages in this synthetic route. First, the synthesis method uses an azide reagent (NaN) 3 ) Explosion is easy to occur, and expansion of production is not facilitated, so that the application prospect is poor. Next, the synthesis method includes a palladium hydrogenation step (Pd/H) 2 ) Has certain danger, introduces heavy metal palladium and has lower safety. Moreover, the synthesis method comprises 6 synthesis steps in total, the route is long, and further space is provided for improvement.
Reference documents:
[1]Lunau N,Seelhorst D,Kahl D,et al.Fluorescently Labeled Substrates for Monitoring 1,3-Fucosyltransferase IX Activity[J].Chemistry-A European Journal,2013.
[2]Lin Y N,Stein D,Lin S W,et al.Chemoenzymatic Synthesis of GDP-L-Fucose Derivatives as Potent and Selectiveα-1,3-Fucosyltransferase Inhibitors[J].Advanced Synthesis&Catalysis,2012,354(9).
disclosure of Invention
In order to solve the problems, the invention provides a synthetic method of a fucose derivative medical intermediate GDP-FAm. The synthesis method provided by the invention reduces the use of azide reagent and palladium, and further improves the yield of the finished product and the operation safety.
In one aspect, the invention provides a synthetic method of a fucose derivative medical intermediate GDP-FAm.
Specifically, the synthesis method comprises the step of carrying out enzymatic reaction by taking 6-amino-alpha-L-galactopyranose as a substrate to obtain GDP-FAm.
Specifically, the synthesis method comprises the step of obtaining the amino-substituted fucose through a mitsunobu reaction and hydrazinolysis.
Generally, the mitsunobu reaction described converts alcohols to a variety of compounds, such as esters, by reaction with triphenylphosphine and diethyl azodicarboxylate (DEAD).
Generally, the hydrazinolysis is a process of producing hydrazine derivatives from various organic compounds with different functional groups under the action of hydrazine and simultaneously obtaining primary amine.
Specifically, the synthesis method comprises substances I, II, III, IV, V and VI in common.
The substance I is L-galactopyranose, namely an initial substrate;
the substance II is 1, 2-bis-O-isopropylidene-alpha-L-galactopyranose;
the substance III is 6-phthalimide-1, 2, 3, 4-bi-O-isopropylidene-alpha-L-galactopyranose;
the substance IV is 6-amino-1, 2;
the substance V is 6-amino-alpha-L-galactopyranose;
and the substance VI is guanosine-5 '-diphosphate and P' - (6-amino-alpha-L-galactopyranose) ester, namely a target product GDP-FAm.
Specifically, the synthetic method comprises the following steps:
specifically, the reaction of the substances II to III is a mitsunobu reaction.
More specifically, the conditions of the mitsunobu reaction are as follows: and dissolving the substance II, phthalimide and triphenylphosphine in tetrahydrofuran, dropwise adding DEAD (diethyl azodicarboxylate) in ice bath, heating to room temperature after dropwise adding, reacting overnight, and performing silica gel column chromatography purification to obtain a colorless oily product.
Further, the conditions of the mitsunobu reaction are as follows: 416mg (1.6 mmol) of 3, 4-bis-O-isopropylidene-. Alpha. -L-galactopyranose, 470.8mg (3.2 mmol) of phthalimide and 1.26g (4.8 mmol) of triphenylphosphine were dissolved in 10mL of tetrahydrofuran, and 836mg (4.8 mmol) of DEAD (diethyl azodicarboxylate) was added dropwise under ice bath, and after completion of the addition, the mixture was warmed to room temperature for overnight reaction, and purified by column chromatography on silica gel to obtain 560mg of a colorless oily product.
Specifically, the reaction of the substance III to the substance IV is hydrazinolysis.
More specifically, the hydrazinolysis condition is that the substance III and hydrazine hydrate are dissolved in ethanol and react for 2 hours at 60 ℃; filtering to remove insoluble substances, spin-drying the filtrate, and purifying by column chromatography to obtain colorless oily product.
Further, the hydrazinolysis conditions are as follows: dissolving 1.3g (3.34 mmol) of 6-phthalimide-1, 2-3, 4-bis-O-isopropylidene-alpha-L-galactopyranose and 330mg (6.68 mmol) of hydrazine hydrate in 30mL of ethanol, and reacting at 60 ℃ for 2 hours to precipitate a large amount of precipitate; filtering to remove insoluble substances, spin-drying the filtrate, and purifying by column chromatography to obtain colorless oily product.
Specifically, the reaction conditions of the substances IV to V are as follows: the material IV is dissolved in trifluoroacetic acid/water solution, reacted for 1 hour at room temperature, and the reaction solution is spin dried to obtain yellow oil.
More specifically, the trifluoroacetic acid/water volume ratio in the trifluoroacetic acid/water solution is 13.2mL/1.32mL.
Preferably, the enzymatic reaction using 6-amino- α -L-galactopyranose as a substrate to obtain GDP-FAm (i.e., substance v to substance vi) includes, but is not limited to: FKP enzyme (L-fucokinase/GDP-fucose pyrophosphorylase), AP enzyme (alkaline phosphatase).
More specifically, the enzymatic reaction using 6-amino-alpha-L-galactopyranose as a substrate to obtain GDP-FAm (i.e., substance V to substance VI) comprises the following steps: adding Tris-HCl (pH 7.0-9.0), manganese chloride, ATP, GTP, 6-amino-alpha-L-galactopyranose and FKP enzyme in turn, and reacting at 0-50 deg.C overnight; centrifuging after the reaction is finished, taking supernate, adding alkaline phosphatase, and reacting at 0-50 ℃ overnight; and after the reaction is finished, centrifuging to take supernatant, purifying by an ion exchange column, and concentrating to obtain a white solid.
Further, the enzymatic reaction using 6-amino- α -L-galactopyranose as a substrate to obtain GDP-FAm (i.e., substance V to substance VI) comprises the steps of: adding 167.65mL of 50mM Tris-HCl (pH8.5) solution, 2mL of 1M manganese chloride aqueous solution, 3.52mL of 0.625M ATP aqueous solution, 5.5mL of 0.4M GTP aqueous solution, 10mL of 200nM 6-amino-alpha-L-galactopyranose solution, 8mL of 7.8mg/ml FKP enzyme solution and reacting at 0-50 ℃ overnight in sequence; centrifuging after the reaction is finished, taking supernate, adding 20mg of alkaline phosphatase, and reacting overnight at the temperature of 0-50 ℃; and after the reaction is finished, centrifuging to take supernatant, purifying by an ion exchange column, and concentrating to obtain a white solid.
In another aspect, the invention provides the use of the aforementioned synthetic method in the preparation of a GDP-FAm derivative drug.
The medicine also comprises other pharmaceutically acceptable carriers or adjuvants.
The invention has the beneficial effects that:
1. the synthesis method provided by the invention comprises 5 steps, and is simple and convenient to operate;
2. the use of azide reagents is reduced, the use of heavy metals and hydrogenation reaction are reduced, and the safety is greatly improved;
3. the synthesis steps are simplified, and the total yield of the route can reach 56%;
4. in the prior art, 6-azido-alpha-L-galactopyranose is generally used as an enzyme reaction substrate when fucose derivatives and GTP (guanosine triphosphate) are subjected to enzymatic reaction, and we firstly find that the 6-amino-alpha-L-galactopyranose can also be subjected to enzymatic reaction to be connected with GDP (guanosine diphosphate) by using the substrate as 6-amino-alpha-L-galactopyranose.
Drawings
FIG. 1 is a NMR spectrum of a colorless oily product obtained in step (1) of example 1.
FIG. 2 is a high resolution mass spectrum of a colorless oily product of step (2) of example 1.
FIG. 3 is a NMR spectrum of a colorless oily product obtained in step (2) of example 1.
FIG. 4 is a high resolution mass spectrum of a colorless oily product of step (3) of example 1.
FIG. 5 is a NMR spectrum of a colorless oily product obtained in step (3) of example 1.
FIG. 6 is a high resolution mass spectrum of a yellow oily product obtained in step (4) of example 1.
FIG. 7 is an ESI-MS spectrum of a white solid obtained in step (5) of example 1.
FIG. 8 is a NMR spectrum of a white solid in step (5) of example 1.
It should be particularly noted that fig. 1 to 8 are diagrams directly obtained by the detection instrument and the calculation software, original coordinate axes and data distribution are retained, and specific data corresponding to the diagrams are disclosed in the embodiments, which do not affect understanding of the technical scheme and determination of technical effects of the present application.
Detailed Description
The present invention will be further illustrated in detail with reference to the following specific examples, which are not intended to limit the present invention but are merely illustrative thereof. The experimental methods used in the following examples, unless otherwise specified, and experimental methods not specified in specific conditions in the examples, are generally commercially available according to conventional conditions, and materials, reagents, and the like used in the following examples, unless otherwise specified.
In the following examples, FKP enzyme (L-fucokinase/GDP-fucose pyrophosphorylase) was prepared according to the following references:
Lin Y N,Stein D,Lin S W,et al.Chemoenzymatic Synthesis of GDP-L-Fucose Derivatives as Potent and Selectiveα-1,3-Fucosyltransferase Inhibitors[J].Advanced Synthesis&Catalysis,2012,354(9).
the alkaline phosphatase preparation method references are:
Lu Z,Chen W,Liu R,et al.A novel method for high-level production of psychrophilic TAB5 alkaline phosphatase[J].Protein Expression&Purification,2010,74(2):217-222.
example 1 Synthesis method of GDP-FAm
The synthetic route of this example is as follows:
the method comprises the following specific steps:
(1) The preparation of 1, 2-bis-O-isopropylidene-alpha-L-galactopyranose shown in formula II comprises the following synthetic route:
the operation steps are as follows: adding 33mL of acetone, 1.23g (9.02 mmol) of zinc chloride and 0.030mL (0.555 mmol) of sulfuric acid into a reaction bottle; the mixture was allowed to stir at room temperature for 5 minutes; 1g of L-galactopyranose of formula I (5.55 mmol) was then added and the reaction mixture stirred overnight (12 h) until the reaction was complete; 3g of Na were added 2 CO 3 And 10mL of water, stirring for 20 minutes, and concentrating the filtered filtrate under vacuum; purification by column chromatography on silica gel gave 1.37g of the product as a colourless oil in the following yield:
the nmr spectrum of the colorless oily product is shown in fig. 1, and the relevant data are as follows:
1 H NMR(400MHz,DMSO)δ＝5.48(d,J＝4.0Hz,1H),4.75-4.72(m,1H),4.61(dd,J＝8.0Hz,1H),4.35(dd,J＝4.0Hz,1H),4.28(dd,J＝4.0,8.0Hz,1H),3.75-3.71(m,1H),3.50-3.56(m,1H),3.56-3.44(m,1H),1.49(s,1H),1.38(s,1H),1.32(s,1H),1.32(s,1H)。
(2) The preparation of 6-phthalimide-1, 2-bis-O-isopropylidene-alpha-L-galactopyranose shown in formula III comprises the following synthetic route:
the method comprises the following operation steps: dissolving 416mg (1.6 mmol) of 3, 4-bis-O-isopropylidene-alpha-L-galactopyranose, 470.8mg (3.2 mmol) of phthalimide and 1.26g (4.8 mmol) of triphenylphosphine in 10mL of tetrahydrofuran, dropwise adding 836mg (4.8 mmol) of DEAD (diethyl azodicarboxylate) under ice bath, heating to room temperature after the dropwise addition, reacting overnight, and purifying by silica gel column chromatography to obtain 560mg of a colorless oily product, wherein the yield is calculated as follows:
the high resolution mass spectrum (ESI +) of the colorless oily product is shown in FIG. 2.
The nmr spectrum is shown in fig. 3, and the relevant data are as follows:
1 H NMR(400MHz,DMSO)δ＝7.96-7.88(m,4H),5.41(d,J＝4.0Hz,1H),4.68(dd,J＝4.0,8.0Hz,1H),4.39-4.35(m,2H),4.25-4.22(m,1H),3.98(dd,J＝8.0,12.0Hz,1H),3.66(dd,J＝8.0,12.0Hz,1H),1.47(s,3H),1.39(s,3H),1.37(s,3H),1.25(s,3H)。
(3) The preparation of 6-amino-1, 2-di-O-isopropylidene-alpha-L-galactopyranose as shown in formula IV has the following synthetic route:
the operation steps are as follows: dissolving 1.3g (3.34 mmol) of 6-phthalimide-1, 2, 3, 4-bis-O-isopropylidene-alpha-L-galactopyranose and 330mg (6.68 mmol) of hydrazine hydrate in 30mL of ethanol, and reacting at 60 ℃ for 2 hours to precipitate a large amount of precipitate; filtering to remove insoluble substances, spin-drying the filtrate, and purifying by column chromatography to obtain colorless oily product 0.78g, with the following yield
The high resolution mass spectrum (ESI +) of the colorless oily product is shown in FIG. 4.
The nmr spectrum is shown in fig. 5, and the relevant data are as follows:
1 H NMR(400MHz,DMSO)δ＝5.37(d,J＝8.0Hz,1H),4.50(dd,J＝8.0Hz,1H),4.25(dd,J＝4.0Hz,1H),4.17(dd,J＝8.0Hz,1H),3.55-3.52(m,1H),2.59-2.57(m,2H),1.39(s,3H),1.27(s,3H),1.21(s,3H),1.21(s,3H)。
(4) The preparation of 6-amino-alpha-L-galactopyranose shown in formula V has the following synthetic route:
the operation steps are as follows: 1g (3.8 mmol) of 6-amino-1, 2-bis-O-isopropylidene-. Alpha. -L-galactopyranose was dissolved in trifluoroacetic acid/water solution (13.2 mL/1.32 mL) and reacted at room temperature for 1 hour, and the reaction solution was spin-dried to obtain 657mg of a yellow oil, the yield was calculated as follows:
the yellow oily product was shown in FIG. 6 by high resolution mass spectrometry (ESI +).
(5) The preparation of GDP-FAm shown in formula VI has the following synthetic route:
the operation steps are as follows: adding 167.65mL of 50mM Tris-HCl (pH 8.5) solution, 2mL of 1M manganese chloride aqueous solution, 3.52mL of 0.625M ATP aqueous solution, 5.5mL of 0.4M GTP aqueous solution, 10mL of 200m6-amino-alpha-L-galactopyranose solution and 8mL of FKP enzyme solution at the temperature of 7.8mg/mL in sequence, and reacting overnight at the temperature of 37 ℃; centrifuging after the reaction is finished, taking supernate, adding 20mg of alkaline phosphatase, and reacting overnight at 37 ℃; after the reaction, the supernatant was centrifuged and purified by ion exchange column to obtain 0.92g of white solid, and the yield was calculated as follows:
the ESI-MS spectrum of the white solid is shown in FIG. 7.
The nmr spectrum is shown in fig. 8, and the relevant data are as follows:
1 H NMR(400MHz,D2O)δ＝8.10(s,1H),5.93(d,J＝4.0Hz,1H),4.98-4.95(m,1H),4.76-4.73(m,1H),4.52-4.50(m,1H),4.37-4.34(m,1H),4.23-4.21(m,2H),3.98-3.94(m,1H),3.92-3.91(m,1H),3.72-3.69(m,1H),3.65-3.61(m,1H),3.32(dd,J＝8.0,12.0Hz,1H),3.24(dd,J＝4.0,12.0Hz,1H)。
Claims (5)
1. a synthetic method of a fucose derivative medical intermediate guanosine-5 '-diphosphate, P' - (6-amino-alpha-L-galactopyranose) ester is characterized by comprising the following steps: taking 6-amino-alpha-L-galactopyranose as a substrate, and obtaining guanosine-5 '-diphosphate and P' - (6-amino-alpha-L-galactopyranose) ester through enzymatic reaction; the synthesis method also comprises the steps of obtaining amino-substituted fucose through mitsunobu reaction and hydrazinolysis;
the synthetic method comprises the following steps:
wherein: the reaction from the substance II to the substance III is a mitsunobu reaction; the reaction from the substance III to the substance IV is hydrazinolysis; the reaction from the substance V to the substance VI is to obtain guanosine-5 '-diphosphate and P' - (6-amino-alpha-L-galactopyranose) ester through enzymatic reaction by taking 6-amino-alpha-L-galactopyranose as a substrate;
the method for preparing guanosine-5 '-diphosphate by using 6-amino-alpha-L-galactopyranose as a substrate through enzymatic reaction, wherein the P' - (6-amino-alpha-L-galactopyranose) ester comprises the following steps: adding Tris-HCl solution, manganese chloride aqueous solution, ATP aqueous solution, GTP aqueous solution, 6-amino-alpha-L-galactopyranose solution and FKP enzyme solution in sequence, and reacting at 0-50 ℃ overnight; centrifuging after the reaction is finished, taking supernate, adding alkaline phosphatase, and reacting at 4-50 ℃ overnight; and after the reaction is finished, centrifuging to take supernatant, purifying by an ion exchange column, and concentrating to obtain a white solid.
2. The synthesis method according to claim 1, wherein the mitsunobu reaction comprises the following steps: dissolving the substance II, phthalimide and triphenylphosphine in tetrahydrofuran, dropwise adding DEAD diethyl azodicarboxylate in ice bath, heating to room temperature after dropwise adding, reacting overnight, and purifying by silica gel column chromatography to obtain colorless oily product.
3. The method of synthesis according to claim 1, wherein said hydrazinolysis comprises the steps of: dissolving a substance III and hydrazine hydrate in ethanol, and reacting for 2 hours at 60 ℃; filtering to remove insoluble substances, spin-drying the filtrate, and purifying by column chromatography to obtain colorless oily product.
4. The method of claim 1, wherein the reaction conditions of substance iv to substance v are: and dissolving the substance IV in trifluoroacetic acid/water solution, reacting at room temperature for 1 hour, and spin-drying the reaction liquid to obtain yellow oily substance.
5. Use of the synthesis method according to any one of claims 1 to 4 for the preparation of a drug derived from guanosine-5 '-diphosphate, P' - (6-amino- α -L-galactopyranose) ester.
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| CN110724209A (en) * | 2018-07-16 | 2020-01-24 | 北京大学 | Fucosylated chondroitin sulfate oligosaccharide and preparation method, composition and application thereof |
| CN112126672A (en) * | 2020-08-19 | 2020-12-25 | 四川大学华西医院 | alpha-L-fucosidase activity determination method, alpha-L-fucosidase diagnostic reagent and application |
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