CN114605366A - Synthesis method and synthesis system for continuous flow preparation of hydroxypropyl pyranotriol - Google Patents
Synthesis method and synthesis system for continuous flow preparation of hydroxypropyl pyranotriol Download PDFInfo
- Publication number
- CN114605366A CN114605366A CN202210455508.5A CN202210455508A CN114605366A CN 114605366 A CN114605366 A CN 114605366A CN 202210455508 A CN202210455508 A CN 202210455508A CN 114605366 A CN114605366 A CN 114605366A
- Authority
- CN
- China
- Prior art keywords
- xylose
- reactor
- mixer
- reaction
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method and a synthetic system for preparing hydroxypropyl pyranotriol by continuous flow, which use a continuous flow process, and an intermediate obtained in the reaction process does not need to be separated, and the method comprises the following steps: and (3) carrying out substitution reaction and reduction reaction on the xylose and the acetylation reagent in a continuous flow reactor under an alkaline condition, then carrying out extraction, liquid separation and desolventizing after quenching to obtain the xylose-containing continuous flow reactor. The synthesis method for preparing the hydroxypropyl pyranotriol by the continuous flow has the advantages of short reaction time, simple and convenient operation, high automation degree, cheap and easily-obtained reagents, good purity of the obtained product (the compound shown in the formula I), less impurities such as caramel and the like, less pungent odor, high transparency, less isomer ratio and high single configuration ratio. Meanwhile, the preparation method has high safety, high productivity and high yield, can reduce environmental pollution and has good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of synthetic chemistry, in particular to a synthetic method and a synthetic system for preparing hydroxypropyl pyranotriol by continuous flow.
Background
Hydroxypropyl pyranotriol, also known as boscalid, english name: Pro-Xylane, CAS number: 439685-79-7, is a cosmetic material with bioactivity. Hydroxypropyl pyranotriol can promote the production of hyaluronic acid and collagen by activating the synthesis of mucopolysaccharides (GAGs); in addition, the hydroxypropyl pyranotriol also has the biological activities of resisting aging, resisting dehydration and the like, and can promote the regeneration of damaged tissues, help to maintain the elasticity of the dermis and prevent skin aging by improving the adhesion degree between the dermis and the epidermis, inducing the synthesis of the structural components of the dermis and the epidermis. Research shows that the hydroxypropyl pyranotriol is easy to biodegrade and can not accumulate in organisms, so that the hydroxypropyl pyranotriol has no toxicity and is considered as an anti-aging new vaccine.
For the synthesis method of the hydroxypropyl pyranotriol, although some documents report at present, column chromatography is often needed, the post-treatment process is complex, and the cost is high.
CavezzaA, boule C, gueguiniata et al in journal [ Bioorganic & medicinal chemistry letters, 2009, 19 (3): 845-849, originally reported that xylose is used as a raw material, and is subjected to condensation reaction with acetylacetone for 12 hours under an alkaline condition, acidification is performed by strong acid cation exchange resin, and carbonyl reduction reaction is performed by borohydride for 12 hours, so that hydroxypropyl pyranotriol is synthesized. Sodium bicarbonate is used as alkali in the reaction, so that the reaction time is long and the yield is low.
Philippe et al reported in journal [ Carbohydr Chem,2014,40:1-10] that xylose as raw material is condensed with acetylacetone under the action of sodium bicarbonate to convert into C-glucoside, and then carbonyl is reduced by heavy metal catalyst Ru/C to synthesize hydroxypropyl pyranotriol. Heavy metal Ru is needed, heavy metal residue cannot be guaranteed, and the influence on the product quality is caused.
Huangdongting and the like are reported in journal [ Guangdong chemical engineering, 2018,45(10):73-74], xylose is used as a raw material, strong-base anion resin is used for replacing common inorganic base, and sodium borohydride is used for reducing carbonyl in the second step to synthesize hydroxypropyl pyranotriol. The reaction solution needs concentrated water, and the product is subjected to column chromatography, so that the yield is only 50%, and the method is not suitable for industrialization.
Wanlongbin et al reported in journal [ foods and pharmaceuticals 2020,22(6),498-499] that hydroxypropyl-pyranotriol is synthesized by using xylose as raw material, potassium hydroxide as alkali and sodium triacetoxyborohydride as reducing agent. Sodium triacetoxyborohydride has weak reducing power, needs excessive reducing agent, has long reaction time and high cost, and the product prepared by the reaction has acetic acid taste and affects the product quality.
Patent CN201910785216.6 reports a method for synthesizing hydroxypropyl pyranotriol by using xylose and ethyl acetoacetate as raw materials and a one-pot method under the promotion of a rare earth metal complex. The reaction is catalyzed by rare earth metal, the quality of the product is influenced by heavy metal residues, and the product quality is influenced by introducing an organic catalyst without adding an impurity removal process.
In addition to the chemical synthesis of hydroxypropyl pyranotriol, the biosynthesis of hydroxypropyl pyranotriol has also been reported, for example: CN202010629023.4 reports the synthesis of hydroxypropyl pyranotriol by a biological enzyme method. And (3) taking xylose and isopropanol as substrates, and taking the screened isopropanol dehydrogenase, hydroxypropyl pyranotriol synthetase and carbonyl reductase as catalysts to synthesize the hydroxypropyl pyranotriol by a one-pot method. In the post-treatment process, multi-step operation procedures such as ultrafiltration are respectively used for removing enzyme, nanofiltration concentration, toluene extraction and the like, and the process is complex.
In addition, patent 202110383018.4 discloses a one-pot synthesis of vitronectin, which is relatively simple, but the obtained product is a yellowish/yellow oil, has strong acetic acid irritating taste, and is not favorable for cosmetic production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a continuous flow synthesis method for preparing hydroxypropyl pyranotriol, which has the advantages of good purity, less impurities such as caramel and the like, less pungent odor, less isomer ratio and high single configuration ratio.
The invention also aims to provide a synthesis system for preparing the hydroxypropyl pyranotriol by continuous flow.
One of the purposes of the invention is realized by adopting the following technical scheme:
a synthetic method for preparing hydroxypropyl pyranotriol by continuous flow, which uses a continuous flow process, and intermediates obtained in the reaction process do not need to be separated, and comprises the following steps: and (3) carrying out substitution reaction and reduction reaction on the xylose and the acetylation reagent in a continuous flow reactor under an alkaline condition, then carrying out extraction, liquid separation and desolventizing after quenching to obtain the xylose-containing continuous flow reactor. The structural formula of the obtained hydroxypropyl pyran triol is shown as the formula I.
More specifically, the reaction scheme is as follows: dissolving a compound D-xylose in a formula II in water or an organic solvent, mixing the compound D-xylose with an acetylation reagent (acetylacetone or ethyl acetoacetate) in a microreactor in the presence of alkali liquor for reaction, directly reducing the obtained intermediate without separation with a reduction reagent in a second reactor, continuously separating liquid after quenching, and desolventizing to obtain a high-concentration product, namely a compound in a formula I, wherein the reaction route is as follows:
the synthesis method for preparing the hydroxypropyl pyranotriol by continuous flow provided by the invention can overcome the problems of safety, environmental protection and space yield existing in the prior art, reduce the generation of impurities, control the proportion of single configuration and be beneficial to improving the activity of the product. Meanwhile, the method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple and convenient operation, high synthesis efficiency, low impurity content, environmental friendliness and suitability for large-scale production.
Further, a synthetic method for preparing hydroxypropyl pyranotriol by continuous flow, which uses a continuous flow process and comprises the following steps:
a first mixing step: respectively pumping the xylose solution, the acylation reagent solution and the alkaline solution into a first mixer through a xylose solution feeding system, an acylation reagent solution feeding system and an alkaline solution feeding system, and mixing to obtain a first mixture;
and (3) substitution reaction steps: the first mixture enters a first reactor for substitution reaction, and a second mixture is obtained after the first mixture reacts for a certain time;
a second mixing step: the second mixture enters a second mixer, a reducing agent is pumped into the second mixer, and a third mixture is obtained after reaction for a certain time;
a reduction reaction step: the third mixture enters a second reactor for reduction reaction to obtain a fourth mixture;
quenching reaction: the fourth mixture enters a third mixer to carry out acid quenching reaction to obtain a fifth mixture;
a separation step: and (4) extracting and separating the fifth mixture in an oil-water continuous separator, and then desolventizing to obtain the oil-water continuous separator.
Further, in the first mixing step, the solute of the xylose solution is xylose, and the solvent is one or any combination of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, glycerol and 1, 3-butanediol, preferably water, methanol, ethanol or n-butanol.
Further, in the acylating reagent solution, the acylating reagent is acetylacetone and/or ethyl acetoacetate, and a solvent for dissolving the acylating reagent is one or any group of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, toluene, xylene, chlorobenzene and dichloromethane, preferably tetrahydrofuran, methanol, ethanol or n-butanol.
Further, the alkali used in the alkaline solution is one or any combination of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, preferably sodium hydroxide, potassium hydroxide or sodium carbonate.
Further, in the second mixing step, the reducing agent is one or any combination of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride; the solvent for dissolving or suspending the reducing agent is one or any combination of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, n-butanol, ethylene glycol and 1, 3-butanediol, preferably water, methanol, ethanol or n-butanol.
Further, in the quenching reaction step, the acid aqueous solution used for quenching reaction is one or any combination of hydrochloric acid aqueous solution, sulfuric acid aqueous solution, sodium hydrogen sulfate aqueous solution, phosphoric acid aqueous solution and citric acid aqueous solution, and preferably hydrochloric acid aqueous solution.
Further, in the separation step, the organic phase used for extraction is selected from water-immiscible organic solvents, such as n-butanol, ethyl acetate, isopropyl acetate, toluene, xylene, chlorobenzene, or any combination thereof, preferably n-butanol.
Further, in the first mixing step, the volume of the solvent in the xylose solution is 2-15 times, preferably 10-12 times, of the volume of the solute xylose; in the acylation reagent solution, the volume of the solvent is 1-15 times, preferably 3 times of the volume of the acylation reagent.
Further, in the first mixing step, the molar ratio of the solute in the xylose solution, the acylating reagent solution and the alkaline solution is 1 (1.0-2.5) to (1.0-2.0), and preferably 1:1.2: 1.2.
Further, in the step of substitution reaction, the reaction temperature is 80-180 ℃, preferably 120-150 ℃, and the reaction time is 30-300 seconds.
Further, in the reduction reaction step, the molar ratio of xylose in the xylose solution to the reducing agent is 1 (1.0-5), the reaction temperature is 20-80 ℃, and the reaction time is 30-300 seconds.
Further, in the reduction reaction step, different reducing agents are selected, and different molar ratios of xylose to the reducing agent are selected; when the reducing agent is sodium borohydride or potassium borohydride, the molar ratio of xylose to the reducing agent is 1 (1.0-1.5); when the reducing agent is sodium triacetoxyborohydride, the molar ratio of the xylose to the reducing agent is 1 (3.0-5.0); the reaction temperature is 30-50 ℃, and the reaction time is 30-300 seconds.
Further, the first mixer, the second mixer and the third mixer are all microchannel reactors, Y-type mixers, T-type mixers or three-way mixers.
Further, the first reactor and the second reactor are microchannel reactors, pipeline reactors, silicon carbide bundled reactors or baffled reactors. More preferably, the first reactor is a microchannel reactor, i.e. the substitution reaction preferably adopts a microchannel reactor; the second reactor is a baffled reactor, namely the baffled reactor is preferred for reduction reaction.
Further, the oil-water continuous separator is an oil-water separator; alternatively, the oil-water continuous separation system comprises a distiller and an extractor.
The second purpose of the invention is realized by adopting the following technical scheme:
a synthetic system for preparing hydroxypropyl pyranotriol by continuous flow is used for one of the purposes, and comprises a feeding system, a first mixer, a first reactor, a second mixer, a second reactor, a third mixer and an oil-water continuous separator which are connected in series in sequence; the feeding system comprises a xylose solution feeding system, an acylation reagent solution feeding system and an alkaline solution feeding system, wherein the xylose solution feeding system, the acylation reagent solution feeding system and the alkaline solution feeding system are respectively connected with the first mixer.
Further, the oil-water continuous separator is an oil-water separator; alternatively, the oil-water continuous separation system comprises a distiller and an extractor.
Further, the first mixer, the second mixer and the third mixer are all microchannel reactors, Y-type mixers, T-type mixers or three-way mixers.
Further, the first reactor and the second reactor are a microchannel reactor, a pipeline reactor, a silicon carbide cluster reactor or a baffle plate reactor; more preferably, the first reactor is a microchannel reactor, i.e. the substitution reaction preferably adopts a microchannel reactor; the second reactor is a baffled reactor, namely the reduction reaction is preferably a baffled reactor.
Compared with the prior art, the invention has the beneficial effects that:
(1) the synthesis method for preparing the hydroxypropyl pyranotriol by continuous flow is a continuous flow one-pot method, and is characterized in that xylose, an acetylation reagent and alkali liquor are respectively pumped into a mixer and a reactor, a reducing agent is pumped after the xylose, the acetylation reagent and the alkali liquor are reserved for a certain time, organic solvent is used for continuous extraction and continuous liquid separation after the reaction is carried out for a certain time, so that a solution of the hydroxypropyl pyranotriol can be obtained, and the hydroxypropyl pyranotriol can be obtained after exsolution. The method has the advantages of short reaction time, simple and convenient operation, high monomer purity, high automation degree, cheap and easily obtained reagents and good industrial application prospect.
(2) The synthesis method for preparing the hydroxypropyl pyranotriol by the continuous flow is prepared by a continuous flow process, and the obtained product (the compound shown in the formula I) has the advantages of good purity, less caramel and other impurities, less pungent smell, high transparency, less isomer ratio and high single configuration ratio. In addition, the method has the advantages of short reaction time of continuous flow, high safety, high productivity and high yield, and can reduce environmental pollution.
(3) The synthesis system for continuously preparing the hydroxypropyl pyranotriol, provided by the invention, is simple to construct, is used for continuously preparing the hydroxypropyl pyranotriol, has high automation degree and simple and convenient operation, and has good industrial application prospect.
Drawings
FIG. 1 is a flow diagram of a synthetic method for the continuous flow preparation of hydroxypropyl pyranotriol provided by an embodiment of the present invention;
FIG. 2 is an HPLC chromatogram of hydroxypyrantriol prepared in example 2 of the present invention;
FIG. 3 is a graph showing a physical alignment of hydroxypyrantriol prepared in example 2 of the present invention and comparative example 1;
FIG. 4 is an HPLC chromatogram of hydroxypyranetriol prepared in comparative example 1.
In fig. 1: 11. a xylose liquor feed system; 12. an alkaline solution feed system; 13. an acylating reagent solution feed system; 14. a first mixer; 15. a first reactor; 16. a second mixer; 17. a second reactor; 18. a third mixer; 19. an oil-water continuous separator.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
The embodiment of the invention provides a synthetic method for preparing hydroxypropyl pyran triol by continuous flow, which comprises the following reaction processes: dissolving a compound D-xylose in a formula II in water or an organic solvent, mixing the compound D-xylose with an acetylation reagent (acetylacetone or ethyl acetoacetate) in a microreactor in the presence of alkali liquor for reaction, directly carrying out reduction reaction with a reduction reagent in a second reactor without separating the obtained intermediate, continuously separating liquid after quenching, and carrying out desolventization to obtain a high-concentration product, namely a compound in a formula I, wherein the reaction route is as follows:
example 1
As shown in fig. 1, a synthesis system for continuous flow preparation of hydroxypropyl pyranotriol comprises a feeding system, a first mixer 14, a first reactor 15, a second mixer 16, a second reactor 17, a third mixer 18 and an oil-water continuous separator 19 which are connected in series in sequence; the feeding system comprises a xylose solution feeding system 11, an acylating reagent solution feeding system 13 and an alkaline solution feeding system 12, wherein the xylose solution feeding system 11, the acylating reagent solution feeding system 13 and the alkaline solution feeding system 12 are respectively connected with a first mixer 14.
In a preferred embodiment, the oil-water continuous separator 19 is an oil-water separator; alternatively, the oil-water continuous separation system comprises a distiller and an extractor.
In a preferred embodiment, the first mixer 14, the second mixer 16, and the third mixer 18 are microchannel reactors, Y-mixers, T-mixers, or three-way mixers.
Further, the first reactor 15 and the second reactor 17 are a microchannel reactor, a pipeline reactor, a silicon carbide cluster reactor or a baffle reactor; more preferably, the first reactor 15 is a microchannel reactor, i.e. the displacement reaction is preferably a microchannel reactor; the second reactor 17 is a baffled reactor, i.e. the reduction reaction is preferably a baffled reactor.
Example 2
As shown in figure 1, the synthesis method for preparing hydroxypropyl pyranotriol by continuous flow comprises the following steps: 3.18 kgD-xylose (compound of formula II) was dissolved in 32L of water, and after stirring for 15 minutes, D-xylose was completely dissolved to prepare phase A of the reaction solution. 2.69kg of sodium carbonate was dissolved in 8L of water to prepare a reaction solution B phase. A phase C of the reaction mixture was prepared by dissolving 2.53kg of acetylacetone in 7.6L of n-butanol. Respectively setting the flow rate of the phase A to be 150mL/min by using a plunger pump; the flow rate of the phase B is 40 mL/min; the flow rate of the C phase is 44 mL/min; is constantly pumped into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor), the reaction temperature being set at 125 ℃ and the retention time being 60 seconds.
Mixing 1kgNaBH4Suspended in 4.5L of water, pumped by a slurry pump into the second mixer 16 at a flow rate of 19mL/min, set the temperature of the second mixer 16 at 50 ℃ and a retention time of 120 seconds, and then passed into the second reactor 17 (baffled reactor), the reaction temperature was 50 ℃ and the retention time was 4 minutes.
10% hydrochloric acid was pumped into the third mixer 18 with the structure at a flow rate of 77mL/min, while n-propanol was pumped into the third mixer 18 at a flow rate of 220mL/min, and after mixing, the mixture was passed into an oil-water separator for liquid separation. Concentrating and desolventizing the organic phase to obtain the target compound hydroxypropyl pyranotriol (shown in formula I), wherein 3.53kg of the product is transparent oily matter with the purity of more than 99 percent and the yield is as follows: 87 percent and the isomer ratio is less than 1 percent.
As shown in fig. 2, the HPLC profile of hydroxypyratriol prepared in example 2 shows relative retention times RT-2.261 min for 1, 4-butanediol, RT-4.881 min for D-xylose, and RT-5.788 min for the desired target configuration.
Example 3
As shown in figure 1, the synthesis method for preparing hydroxypropyl pyranotriol by continuous flow comprises the following steps:
3 kgD-xylose (formula II compound) was dissolved in 28L water, and stirred for 15 minutes to completely dissolve D-xylose, thereby preparing phase A of the reaction solution. 3.31kg of potassium carbonate was dissolved in 10L of water to prepare a reaction solution B phase. 3.12kg of ethyl acetoacetate was dissolved in 8.3L of n-butanol to prepare a reaction solution C phase. Respectively setting the flow rate of the phase A to be 150mL/min by using a plunger pump; the flow rate of the phase B is 40 mL/min; the flow rate of the C phase is 44 mL/min; is constantly pumped into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor), the reaction temperature being set at 125 ℃ and the retention time being 40 seconds.
Adding 0.98kgNaBH4Suspended in 4.5L of water, pumped by a slurry pump into the second mixer 16 at a flow rate of 19mL/min, set the temperature of the second mixer 16 at 50 ℃ and a retention time of 120 seconds, and then passed into the second reactor 17 (baffled reactor), the reaction temperature was 50 ℃ and the retention time was 4 minutes.
10% hydrochloric acid was pumped into the third mixer 18 with the structure at a flow rate of 70mL/min, while n-propanol was pumped into the third mixer 18 at a flow rate of 200mL/min, and after mixing, the mixture was passed into an oil-water separator for liquid separation. Concentrating and desolventizing the organic phase to obtain the target compound hydroxypropyl pyranotriol (shown in formula I), wherein the obtained product is 3.27kg of transparent oily matter, the purity is more than 99%, and the yield is as follows: 85 percent and the isomer ratio is less than 1 percent.
Example 4
As shown in figure 1, the synthesis method for preparing hydroxypropyl pyranotriol by continuous flow comprises the following steps:
9 kgD-xylose (formula II compound) was dissolved in 84L ethanol, and stirred for 30 minutes to completely dissolve D-xylose, thereby preparing phase A of the reaction solution. A phase B of the reaction mixture was prepared by dissolving 2.88kg of sodium hydroxide in 30L of water. A reaction solution C phase was prepared by dissolving 7.2kg of acetylacetone in 25L of ethanol. Respectively setting the flow rate of the phase A to be 450mL/min by using a plunger pump; the flow rate of the phase B is 120 mL/min; the flow rate of the C phase is 132 mL/min; is constantly pumped into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor), the reaction temperature being set at 125 ℃ and the retention time being 40 seconds.
3.2kgNaBH4Suspended in 15L of water, pumped by a slurry pump into the second mixer 16 at a flow rate of 60mL/min, set the temperature of the second mixer 16 at 50 ℃ and a retention time of 110 seconds, and then entered the second reactor 17 (baffled reactor) at a reaction temperature of 50 ℃ and a retention time of 4 minutes.
Pumping 10% hydrochloric acid into a third mixer 18 with a component at a flow rate of 200mL/min, after the reaction is finished, distilling the solution under reduced pressure to remove ethanol, extracting with n-propanol for three times, combining organic phases, and performing reduced pressure concentration and desolventization to obtain a target compound, namely hydroxypropyl pyranotriol (shown in formula I), wherein 10kg of the product is a transparent oily substance with the purity of more than 99 percent, and the yield is as follows: 87 percent and the isomer ratio is less than 1 percent.
Example 5
As shown in figure 1, the synthesis method for preparing hydroxypropyl pyranotriol by continuous flow comprises the following steps:
1.8 kgD-xylose (compound of formula II) was dissolved in 16.8L ethanol and stirred for 30 minutes to completely dissolve D-xylose, thereby preparing phase A of the reaction mixture. 576g of sodium hydroxide was dissolved in 6L of water to prepare a reaction solution B phase. A phase C of the reaction mixture was prepared by dissolving 1.44kg of ethyl acetoacetate in 5L of ethanol. Respectively setting the flow rate of the phase A to be 450mL/min by using a plunger pump; the flow rate of the phase B is 120 mL/min; the flow rate of the C phase is 132 mL/min; is constantly pumped into the first mixer 14 and then into the first reactor 15 at a set flow rate, the reaction temperature being set at 125 ℃ and the retention time being 40 seconds.
3.5kg of NaBH (OAc)3Suspended in 3L of water, pumped into the second mixer 16 by a slurry pump at a flow rate of 60mL/min, set the temperature of the second mixer 16 at 50 ℃ and the retention time at 110 seconds, and then into the second reactor 17 (baffled reactor), the reaction temperature at 50 ℃ and the retention time at 4 minutes.
Pumping 10% hydrochloric acid into a third mixer 18 with a component at a flow rate of 200mL/min, after the reaction is finished, distilling the solution under reduced pressure to remove ethanol, extracting with n-propanol for three times, combining organic phases, and performing reduced pressure concentration and desolventization to obtain a target compound hydroxypropyl pyranotriol (shown in formula I), wherein 1.9kg of the product is a transparent oily substance with the purity of more than 99%, and the yield is as follows: 83% and the isomer ratio is less than 1%.
Comparative example 1
The operation is carried out according to example 1 of a one-pot synthesis method of vitronectin in patent 202110383018.4, and the specific steps are as follows: 500g of ethanol, 30g (0.2mol) of xylose, 0.17g (2mmol) of sodium bicarbonate and 26g (0.2mol) of ethyl acetoacetate were sequentially added into a 1000mL reaction flask, the mixture was stirred and heated to 60 ℃ to continue the reaction for 1 hour, and the reaction solution was detected by TLC until xylose was almost disappeared (GF254 silica gel plate, developing solvent dichloromethane: methanol 4:1, 20% ethanol sulfate solution was used for color development). Then, 11.3g (0.3mol) of sodium borohydride is dropwise added at 0 ℃, after stirring uniformly, the mixture reacts at 50 ℃ for 24 hours, 2N hydrochloric acid is slowly dropwise added, the pH value is adjusted to be neutral, then ethyl acetate is used for extracting and separating liquid, an organic layer is collected and dried in a spinning mode, and the vitreochrome is obtained and is caramel oily matter, the purity is 12.7%, the yield is 77%, and the isomer ratio is 46.8%. As shown in fig. 4, the HPLC profile of the hydroxypyrantriol prepared in comparative example 1 shows that the relative retention time RT-5.793 min is the desired target configuration product.
As shown in FIG. 3, which is a real figure of hydroxypropyl pyranotriol obtained in example 2 of the present invention and comparative example 1, it can be seen that the product color of glassy color obtained in comparative example 1 is caramel color and sour taste is heavy, mainly because the reaction time of comparative example 1 is long. In contrast, in example 2 of the present invention, which employs a continuous flow synthesis method, the obtained glass color is a colorless transparent solution due to the glass color, and the acetic acid taste is very light and almost no sour taste, which is a very important improvement for cosmetics. The product object diagrams of examples 3 to 5 are similar to those of example 1, and are not described again.
The synthesis method for continuously preparing the hydroxypropyl pyranotriol, provided by the embodiment of the invention, has the advantages of short reaction time, simplicity and convenience in operation, high automation degree, cheap and easily-obtained reagents, good purity of the obtained product (the compound shown in the formula I), less impurities such as caramel and the like, less pungent smell, high transparency, less isomer ratio and high single configuration ratio. Meanwhile, the preparation method has high safety, high productivity and high yield, can reduce environmental pollution and has good industrial application prospect.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. A synthetic method for preparing hydroxypropyl pyranotriol by continuous flow is characterized in that a continuous flow process is used, and an intermediate obtained in the reaction process does not need to be separated, and comprises the following steps: and (3) carrying out substitution reaction and reduction reaction on the xylose and the acetylation reagent in a continuous flow reactor under an alkaline condition, then carrying out extraction, liquid separation and desolventizing after quenching to obtain the xylose-containing continuous flow reactor.
2. The continuous-flow synthesis process for the preparation of hydroxypropylpyranotriol according to claim 1, characterized by using a continuous-flow process comprising the following steps:
a first mixing step: respectively pumping the xylose solution, the acylation reagent solution and the alkaline solution into a first mixer through a xylose solution feeding system, an acylation reagent solution feeding system and an alkaline solution feeding system, and mixing to obtain a first mixture;
and (3) substitution reaction steps: the first mixture enters a first reactor for substitution reaction, and a second mixture is obtained after the first mixture reacts for a certain time;
a second mixing step: the second mixture enters a second mixer, a reducing agent is pumped into the second mixer, and a third mixture is obtained after reaction for a certain time;
a reduction reaction step: the third mixture enters a second reactor for reduction reaction to obtain a fourth mixture;
quenching reaction: the fourth mixture enters a third mixer to carry out acid quenching reaction to obtain a fifth mixture;
a separation step: and (4) extracting and separating the fifth mixture in an oil-water continuous separator, and then desolventizing to obtain the oil-water continuous separator.
3. The continuous-flow synthesis process for preparing hydroxypropyl pyranotriol according to claim 2, wherein in the first mixing step, the solute of the xylose solution is xylose, and the solvent is one or any combination of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, glycerol, 1, 3-butanediol; in the acylation reagent solution, an acylation reagent is acetylacetone and/or ethyl acetoacetate, and a solvent for dissolving the acylation reagent is one or any combination of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, toluene, xylene, chlorobenzene and dichloromethane; the alkali used in the alkaline solution is one or any combination of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, magnesium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate and dipotassium hydrogen phosphate;
in the second mixing step, the reducing agent is one or any combination of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride, and the solvent for dissolving or suspending the reducing agent is one or any combination of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, n-butanol, ethylene glycol and 1, 3-butanediol;
in the quenching reaction step, the acid aqueous solution used for the quenching reaction is one or any combination of hydrochloric acid aqueous solution, sulfuric acid aqueous solution, sodium bisulfate aqueous solution, phosphoric acid aqueous solution and citric acid aqueous solution;
in the separation step, the organic phase used for extraction is one or any combination of n-butanol, ethyl acetate, isopropyl acetate, toluene, xylene and chlorobenzene.
4. The continuous-flow synthesis process for the preparation of hydroxypropylpyranotriol according to claim 2, wherein in the first mixing step, the solute of xylose solution is xylose and the solvent is water, methanol, ethanol or n-butanol; in the acylation reagent solution, a solvent for dissolving the acylation reagent is tetrahydrofuran, methanol, ethanol or n-butanol; the alkali used in the alkaline solution is sodium hydroxide, potassium hydroxide or sodium carbonate;
in the second mixing step, the solvent dissolving or suspending the reducing agent is water, methanol, ethanol or n-butanol;
in the quenching reaction step, the acid aqueous solution used for the quenching reaction is hydrochloric acid aqueous solution;
in the separation step, the organic phase used for extraction is n-butanol.
5. The continuous-flow synthesis method for preparing hydroxypropyl pyranotriol according to claim 2, wherein in the first mixing step, the volume of the solvent in the xylose solution is 2 to 15 times of the volume of the solute xylose, and the volume of the solvent in the acylating reagent solution is 1 to 15 times of the volume of the acylating reagent;
in the first mixing step, the molar ratio of the solute in the xylose solution, the acylating reagent solution and the alkaline solution is 1 (1.0-2.5) to 1.0-2.0;
in the step of substitution reaction, the reaction temperature is 80-180 ℃, and the reaction time is 30-300 seconds;
in the reduction reaction step, the molar ratio of xylose to the reducing agent in the xylose solution is 1 (1.0-5), the reaction temperature is 20-80 ℃, and the reaction time is 30-300 seconds.
6. The continuous-flow synthesis process for the preparation of hydroxypropylpyranotriol according to claim 2, wherein in the first mixing step, the volume of solvent in the xylose solution is 10 to 12 times the volume of solute xylose; in the acylation reagent solution, the volume of the solvent is 3 times of that of the acylation reagent;
in the first mixing step, the molar ratio of solutes in the xylose solution, the acylating reagent solution and the alkaline solution is 1:1.2: 1.2;
in the step of substitution reaction, the reaction temperature is 120-150 ℃, and the reaction time is 30-300 seconds;
in the reduction reaction step, when the reducing agent is sodium borohydride or potassium borohydride, the molar ratio of xylose to the reducing agent is 1 (1.0-1.5); when the reducing agent is sodium triacetoxyborohydride, the molar ratio of the xylose to the reducing agent is 1 (3.0-5.0); the reaction temperature is 30-50 ℃, and the reaction time is 30-300 seconds.
7. The continuous-flow synthesis process for the preparation of hydroxypropyl triol of claim 2, wherein the first mixer, the second mixer and the third mixer are each a microchannel reactor, a Y-mixer, a T-mixer or a three-way mixer;
the first reactor and the second reactor are respectively a microchannel reactor, a pipeline reactor, a silicon carbide cluster reactor or a baffle plate reactor;
the oil-water continuous separator is an oil-water separator; alternatively, the oil-water continuous separation system comprises a distiller and an extractor.
8. A synthesis system for preparing hydroxypropyl pyranotriol by continuous flow, which is used in the synthesis method of any one of claims 1 to 7 and comprises a feeding system, a first mixer, a first reactor, a second mixer, a second reactor, a third mixer and an oil-water continuous separator which are connected in series in sequence; the feeding system comprises a xylose solution feeding system, an acylation reagent solution feeding system and an alkaline solution feeding system, wherein the xylose solution feeding system, the acylation reagent solution feeding system and the alkaline solution feeding system are respectively connected with the first mixer.
9. The continuous-flow hydroxypropyl pyranotriol synthesis system of claim 8, wherein the continuous oil-water separator is an oil-water separator; alternatively, the oil-water continuous separation system comprises a distiller and an extractor.
10. The continuous-flow synthesis system for the preparation of hydroxypropyl triol of claim 8, wherein the first mixer, the second mixer and the third mixer are each a microchannel reactor, a Y-mixer, a T-mixer or a three-way mixer;
the first reactor and the second reactor are respectively a micro-channel reactor, a pipeline reactor, a silicon carbide cluster reactor or a baffle plate reactor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210455508.5A CN114605366B (en) | 2022-04-28 | 2022-04-28 | Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210455508.5A CN114605366B (en) | 2022-04-28 | 2022-04-28 | Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114605366A true CN114605366A (en) | 2022-06-10 |
| CN114605366B CN114605366B (en) | 2023-10-10 |
Family
ID=81869357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210455508.5A Active CN114605366B (en) | 2022-04-28 | 2022-04-28 | Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114605366B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114835666A (en) * | 2022-06-30 | 2022-08-02 | 天津泰普制药有限公司 | Continuous synthesis method of hydroxypropyl tetrahydropyrane triol |
| CN117229248A (en) * | 2023-08-21 | 2023-12-15 | 浙江晟格生物科技有限公司 | Method for preparing and purifying vitronectin by using solid alkali |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210163384A1 (en) * | 2019-12-02 | 2021-06-03 | Yale University | Compositions and Methods for Reducing Enones to Saturated Alcohols |
| CN113773291A (en) * | 2021-10-09 | 2021-12-10 | 上海昕凯医药科技有限公司 | Improved synthesis method of vitronectin as effective component of cosmetics |
-
2022
- 2022-04-28 CN CN202210455508.5A patent/CN114605366B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210163384A1 (en) * | 2019-12-02 | 2021-06-03 | Yale University | Compositions and Methods for Reducing Enones to Saturated Alcohols |
| CN113773291A (en) * | 2021-10-09 | 2021-12-10 | 上海昕凯医药科技有限公司 | Improved synthesis method of vitronectin as effective component of cosmetics |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114835666A (en) * | 2022-06-30 | 2022-08-02 | 天津泰普制药有限公司 | Continuous synthesis method of hydroxypropyl tetrahydropyrane triol |
| CN117229248A (en) * | 2023-08-21 | 2023-12-15 | 浙江晟格生物科技有限公司 | Method for preparing and purifying vitronectin by using solid alkali |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114605366B (en) | 2023-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114605366B (en) | Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow | |
| CN101851151B (en) | Method for preparing cyclohexanol by using cyclohexene | |
| CN108530279B (en) | Synthesis method of pseudo ionone | |
| CN107337592B (en) | Method for synthesizing muscone by using beta-methyl glutarate monomethyl ester | |
| CN112094187A (en) | Method for preparing and separating levulinic acid from fructose | |
| CN101941958B (en) | Method for preparing 5-hydroxymethyl furfural and 2,5-furandimethanol simultaneously | |
| CN114105914B (en) | Method for preparing 2, 5-furandimethanol by using 5-chloromethyl furfural | |
| CN116947795B (en) | Continuous synthesis method of S-hydroxypropyl tetrahydropyran triol | |
| CN102643185B (en) | Green and simple preparation method for 2,3,5-trimethylbenzoquinone (TMBQ) | |
| CN105833909A (en) | (S)-1-(2-hydrox-1-phenethyl)thiourea modified Cr-Anderson heteropolyacid catalyst, and preparation method and application thereof | |
| CN105732373B (en) | The method that one kind prepares the phenylbutyrate of (R) 2 hydroxyl 4 | |
| CN105833910A (en) | (R)-1-(2-hydrox-1-phenethyl)thiourea modified Cr-Anderson heteropolyacid catalyst, and preparation method and application thereof | |
| CN103497138B (en) | A kind ofly utilize zinc chloride, method that POTASSIUM BOROHYDRIDE prepares cis-hexahydroisoindoline | |
| CN103554005A (en) | Novel simple synthesis method of L-5-hydroxytryptophan | |
| CN102040527A (en) | Preparation method of N,N-benzyl diphenylamine | |
| CN111499497A (en) | Preparation method of thymol | |
| CN106397117B (en) | Reductive alcoholization and resolution method of cyclohexyl phenyl ketone | |
| US5618985A (en) | Process for the preparation of 2-n-butyl-2-ethyl-1,3-propane diol | |
| CN100999741A (en) | Process of extracting mannitol using glucose mother liquid | |
| CN111718245B (en) | Method for preparing deuterated chemicals through photocatalytic decarboxylation conversion | |
| CN108047001A (en) | A kind of method for synthesizing 2,5- xylenols | |
| CN112439454B (en) | RT base condensation catalyst and preparation method thereof | |
| CN211645082U (en) | Device for preparing cyclohexylmethanol by benzyl alcohol hydrogenation | |
| CN115073268B (en) | 3, 3-trifluoropropanol and preparation method thereof | |
| WO2022117071A1 (en) | Method for synthesizing benzyl ether from polyhydric phenol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |