CN114605366B - Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow - Google Patents
Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow Download PDFInfo
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- CN114605366B CN114605366B CN202210455508.5A CN202210455508A CN114605366B CN 114605366 B CN114605366 B CN 114605366B CN 202210455508 A CN202210455508 A CN 202210455508A CN 114605366 B CN114605366 B CN 114605366B
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- 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
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Abstract
The invention discloses a synthesis method and a synthesis system for preparing hydroxypropyl pyrantriol by continuous flow, which use a continuous flow process, 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 xylose and an acetylating reagent in a continuous flow reactor under alkaline conditions, then carrying out extraction, liquid separation and desolventizing after quenching. The synthesis method for preparing hydroxypropyl pyrantriol by continuous flow provided by the invention has the advantages of short reaction time, simple and convenient operation, high automation degree, low price and easy obtainment of reagents, good purity of the obtained product (the compound shown in the formula I), less impurities such as caramel, 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 pyrantriol by continuous flow.
Background
Hydroxypropyl pyrantriol, also known as vitronectin, english name: pro-Xylane, CAS number: 439685-79-7 is a cosmetic raw material with bioactivity. Hydroxypropyl pyrantriols can promote the production of hyaluronic acid and collagen by activating the synthesis of mucopolysaccharides (GAGs); in addition, the hydroxypropyl pyrantriol has the biological activities of resisting aging, resisting dehydration and the like by improving the adhesiveness between dermis and epidermis, inducing the synthesis of dermis and epidermis structural components, promoting the regeneration of damaged tissues, helping to maintain the elasticity of dermis and preventing skin aging. Studies have shown that hydroxypropyl pyrantriol is readily biodegradable and does not accumulate in organisms and is therefore non-toxic and considered to be anti-ageing.
Although some literature reports exist on the synthesis method of hydroxypropyl pyrantriol at present, column chromatography is often needed, the post-treatment process is complex, and the cost is high.
Cavezza, boulle C, gueguininiata et al, journal [ Bioorganic & medicinal chemistry letters,2009, 19 (3): 845-849 reports that xylose is used as raw material, and is condensed with acetylacetone for 12 hours under alkaline condition, acidified by strong acid cation exchange resin, and then reduced by borohydride for 12 hours to synthesize hydroxypropyl pyrantriol. Sodium bicarbonate is used as alkali in the reaction, so that the reaction time is long and the yield is low.
Philipe et al report in journal [ carbohydrate Chem,2014,40:1-10], and use xylose as a raw material, and undergo condensation reaction with acetylacetone under the action of sodium bicarbonate to convert into C-glycoside, and then undergo reduction of carbonyl group by heavy metal catalyst Ru/C to synthesize hydroxypropyl pyrantriol. Heavy metal Ru is needed, heavy metal residue cannot be guaranteed, and the quality of products is affected.
Huang Dongting et al in journal [ Guangdong chemical industry, 2018,45 (10): 73-74] reported that hydroxypropylpyrantriol was synthesized from xylose as a raw material by using a strongly basic anion resin instead of a common inorganic base and reducing the carbonyl group with sodium borohydride in the second step. The reaction liquid needs concentrated water, and the yield of column chromatography products is only 50%, which is not suitable for industrialization.
Wang Chang et al in journal [ food and medicine, 2020,22 (6), 498-499] report that hydroxypropylpyrantriol is synthesized from xylose as a raw material, potassium hydroxide as a base, and sodium triacetoxyborohydride as a reducing agent. Sodium triacetoxyborohydride has weak reducing capability, needs excessive reducing agent, has long reaction time and high cost, and the product prepared by the reaction has acetic acid taste and influences the product quality.
Patent CN201910785216.6 reports a method for synthesizing hydroxypropyl pyrantriol by a one-pot method under the promotion of rare earth metal complexes by taking xylose and ethyl acetoacetate as raw materials. The reaction is catalyzed by rare earth metal, the quality of the product is affected by heavy metal residue, and the organic catalyst is introduced, so that the impurity removal process is not increased, and the quality of the product is affected.
In addition to the chemical synthesis of hydroxypropyl pyrantriol, there are also reports of the biosynthetic preparation of hydroxypropyl pyrantriol, for example: CN202010629023.4 reports the synthesis of hydroxypropyl pyrantriol using a bioenzyme method. The method takes xylose and isopropanol as substrates, and uses screened isopropanol dehydrogenase, hydroxypropyl pyrantriol synthase and carbonyl reductase as catalysts to synthesize the hydroxypropyl pyrantriol by a one-pot method. In the post-treatment process, enzyme is removed by ultrafiltration, nanofiltration concentration is carried out, toluene extraction and other multi-step operation procedures are carried out, and the process is complex.
In addition, patent 202110383018.4 discloses a method for synthesizing vitronectin by a one-pot method, which is relatively simple in steps, but the obtained product is light yellow/yellow oily matter, has strong acetic acid-stimulated taste, and is unfavorable for cosmetic production.
Disclosure of Invention
In order to overcome the defects of the prior art, one of the purposes of the invention is to provide a synthesis method for preparing hydroxypropyl pyrantriol by continuous flow, wherein the obtained hydroxypropyl pyrantriol has good purity, less impurities such as caramel, less pungent smell, less isomer ratio and high single configuration ratio.
The second object of the invention is to provide a synthesis system for continuous flow preparation of hydroxypropyl pyrantriol.
One of the purposes of the invention is realized by adopting the following technical scheme:
a synthesis method for preparing hydroxypropyl pyrantriol by continuous flow, which uses a continuous flow process, and an intermediate obtained in the reaction process does not need to be separated, comprises the following steps: and (3) carrying out substitution reaction and reduction reaction on xylose and an acetylating reagent in a continuous flow reactor under alkaline conditions, then carrying out extraction, liquid separation and desolventizing after quenching. The structural formula of the obtained hydroxypropyl pyrantriol is shown as the following formula I.
More specifically, the reaction scheme is as follows: dissolving a compound D-xylose of a formula II in water or an organic solvent, mixing with an acetylating reagent (acetylacetone or ethyl acetoacetate) in a micro-reactor in the presence of alkali liquor for reaction, directly reducing the obtained intermediate with a reducing reagent in a second reactor without separation, quenching and continuously separating liquid, and obtaining a high-concentration product, namely the compound of the formula I after desolventizing, wherein the reaction route is as follows:
the synthesis method for preparing hydroxypropyl pyrantriol by continuous flow provided by the invention can overcome the problems of safety, environmental protection and space yield existing in the prior preparation technology, reduce impurity generation, can control single configuration proportion, and is beneficial to improving the activity of products. 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 and environmental friendliness, and is suitable for mass production.
Further, a synthesis method for preparing hydroxypropyl pyrantriol by continuous flow, which uses a continuous flow process, comprises the following steps:
a first mixing step: pumping the xylose solution, the acylating reagent solution and the alkaline solution into a first mixer through a xylose solution feeding system, an acylating reagent solution feeding system and an alkaline solution feeding system respectively, and mixing to obtain a first mixture;
substitution reaction step: the first mixture enters a first reactor to carry out substitution reaction, and after a certain period of reaction, a second mixture is obtained;
a second mixing step: the second mixture enters a second mixer, a reducing agent is pumped into the second mixer, and after a certain period of reaction, a third mixture is obtained;
a reduction reaction step: the third mixture enters a second reactor for reduction reaction to obtain a fourth mixture;
quenching reaction steps: the fourth mixture enters a third mixer to carry out acid quenching reaction to obtain a fifth mixture;
separating: and (3) the fifth mixture enters an oil-water continuous separator for extraction, liquid separation and desolventizing, so that the oil-water continuous separator is obtained.
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 the 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, and 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, and is preferably water, methanol, ethanol or n-butanol.
Further, in the quenching reaction step, the aqueous acid solution used in the quenching reaction is one or any combination of aqueous hydrochloric acid, aqueous sulfuric acid, aqueous sodium bisulfate, aqueous phosphoric acid and aqueous citric acid, preferably aqueous hydrochloric acid.
Further, in the separation step, the organic phase used for extraction is selected from water-immiscible organic solvents such as one or any combination of n-butanol, ethyl acetate, isopropyl acetate, toluene, xylene, chlorobenzene, preferably n-butanol.
Further, in the first mixing step, the volume of the solvent in the xylose solution is 2 to 15 times, preferably 10 to 12 times, the volume of the solute xylose; in the acylating agent solution, the volume of the solvent used is 1 to 15 times, preferably 3 times, the volume of the acylating agent.
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): (1.0-2.0), preferably 1:1.2:1.2.
Further, in the substitution reaction step, the reaction temperature is 80 to 180 ℃, preferably 120 to 150 ℃, and the reaction time is 30 to 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 agents 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 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 each a microchannel reactor, a pipeline reactor, a silicon carbide cluster reactor, or a baffle reactor. More preferably, the first reactor is a microchannel reactor, i.e. the substitution reaction preferably employs a microchannel reactor; the second reactor is a baffled reactor, i.e. the reduction reaction is preferably a baffled reactor.
Further, the oil-water continuous separator is an oil-water separator; alternatively, the continuous oil-water separation system comprises a distiller and an extractor.
The second purpose of the invention is realized by adopting the following technical scheme:
a synthesis system for preparing hydroxypropyl pyrantriol by continuous flow, which 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 sequentially connected in series; the feeding system comprises a xylose solution feeding system, an acylating reagent solution feeding system and an alkaline solution feeding system, wherein the xylose solution feeding system, the acylating 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 continuous oil-water 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 all microchannel reactors, pipeline reactors, silicon carbide cluster reactors or baffle plate reactors; more preferably, the first reactor is a microchannel reactor, i.e. the substitution reaction preferably employs a microchannel reactor; the second reactor is a baffled reactor, i.e. the reduction reaction is preferably a baffled reactor.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a synthesis method for preparing hydroxypropyl pyrantriol by continuous flow, which is a continuous flow one-pot method, xylose, an acetylation reagent and alkali liquor are respectively pumped into a mixer and a reactor, after a certain period of time is reserved, a reducing agent is pumped into the mixer and the reactor, after a certain period of time is reacted, the mixture is continuously extracted by an organic solvent and is continuously separated, so that a hydroxypropyl pyrantriol solution is obtained, and the hydroxypropyl pyrantriol is obtained after desolventizing. The method has the advantages of short reaction time, simple and convenient operation, high monomer purity, high automation degree, low price and easy acquisition of reagents, and good industrial application prospect.
(2) The synthesis method for preparing hydroxypropyl pyrantriol by continuous flow provided by the invention adopts 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 odor, high transparency, less isomer ratio and high single configuration ratio. In addition, the invention has the advantages of short continuous flow reaction time, high safety, high productivity and high yield, and can reduce environmental pollution.
(3) The synthesis system for preparing the hydroxypropyl pyrantriol by the continuous flow provided by the invention is simple to construct, is used for continuous flow preparation of the hydroxypropyl pyrantriol, has high degree of automation, is simple and convenient to operate, and has good industrial application prospect.
Drawings
FIG. 1 is a flow chart of a method for synthesizing hydroxypropyl pyrantriol by continuous flow provided by the embodiment of the invention;
FIG. 2 is an HPLC chart of hydroxypyrotriol prepared in example 2 of the present invention;
FIG. 3 is a diagram showing a comparative example of the hydroxypyrotriol prepared in example 2 of the present invention and comparative example 1;
FIG. 4 is an HPLC chart of hydroxypyrotriol prepared in comparative example 1.
In fig. 1: 11. a xylose solution 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 will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below.
The embodiment of the invention provides a synthesis method for preparing hydroxypropyl pyrantriol by continuous flow, which comprises the following reaction flow: dissolving a compound D-xylose of a formula II in water or an organic solvent, mixing with an acetylating reagent (acetylacetone or ethyl acetoacetate) in a microreactor in the presence of alkali liquor for reaction, directly carrying out reduction reaction with a reducing reagent in a second reactor without separation of the obtained intermediate, and then quenching and continuously separating the solution for desolventizing to obtain a high-concentration product compound of the formula I, wherein the reaction route is as follows:
example 1
As shown in fig. 1, a synthesis system for preparing hydroxypropyl pyrantriol by continuous flow 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 sequentially connected in series; the feed system comprises a xylose solution feed system 11, an acylating reagent solution feed system 13 and an alkaline solution feed system 12, the xylose solution feed system 11, the acylating reagent solution feed system 13 and the alkaline solution feed system 12 being connected to a first mixer 14, respectively.
As a preferred embodiment, the oil-water continuous separator 19 is an oil-water separator; alternatively, the continuous oil-water separation system includes a distiller and an extractor.
As a preferred embodiment, the first mixer 14, the second mixer 16 and the third mixer 18 are all microchannel reactors, Y-mixers, T-mixers or three-way mixers.
Further, the first reactor 15 and the second reactor 17 are each 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 substitution reaction preferably employs 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 fig. 1, a synthetic method for preparing hydroxypropyl pyrantriol by continuous flow comprises the following steps: 3.18-kgD-xylose (compound of formula II) was dissolved in 32L of water, stirred for 15 minutes, and D-xylose was completely dissolved to prepare a reaction solution A phase. 2.69kg of sodium carbonate was dissolved in 8L of water to prepare a reaction liquid phase B. 2.53kg of acetylacetone was dissolved in 7.6L of n-butanol to prepare a reaction solution C phase. Setting the flow rate of the phase A to 150mL/min by using plunger pumps respectively; the flow rate of the B-phase flow is 40mL/min; the flow rate of the C phase is 44mL/min; is pumped constantly into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor) with a reaction temperature set at 125℃and a residence time of 60 seconds.
1kg of NaBH 4 Suspending in 4.5L water, pumping into second mixer 16 at 19mL/min by slurry pump, setting the temperature of second mixer 16 to 50deg.C, keeping for 120 seconds, and introducing into second reactor 17 (baffle reactor) at 50deg.C for retentionThe interval is 4 minutes.
10% hydrochloric acid is pumped into the third mixer 18 with the components at a flow rate of 77mL/min, meanwhile, n-propanol is pumped into the third mixer 18 at a flow rate of 220mL/min, and the mixture is fed into an oil-water separator for liquid separation. Concentrating and desolventizing the organic phase to obtain the target compound hydroxypropyl pyrantriol (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: 87%, isomer ratio less than 1%.
As shown in fig. 2, the HPLC profile of the hydroxypyrol prepared in example 2, with relative retention time rt= 2.261min for 1, 4-butanediol, rt= 4.881min for D-xylose, and rt= 5.788min for the desired target configuration product.
Example 3
As shown in fig. 1, a synthetic method for preparing hydroxypropyl pyrantriol by continuous flow comprises the following steps:
3 kgD-xylose (a compound of formula II) was dissolved in 28L of water, stirred for 15 minutes, and D-xylose was completely dissolved to prepare a reaction solution A phase. 3.31kg of potassium carbonate was dissolved in 10L of water to prepare a reaction liquid phase B. 3.12kg of ethyl acetoacetate was dissolved in 8.3L of n-butanol to prepare a reaction liquid phase C. Setting the flow rate of the phase A to 150mL/min by using plunger pumps respectively; the flow rate of the B-phase flow is 40mL/min; the flow rate of the C phase is 44mL/min; is pumped constantly into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor) with a reaction temperature set at 125℃and a retention time of 40 seconds.
Will be 0.98kg NaBH 4 Suspended in 4.5L of water, pumped into the second mixer 16 by a slurry pump at a flow rate of 19mL/min, the temperature of the second mixer 16 was set to 50 c, the retention time was 120 seconds, and then entered into the second reactor 17 (baffle reactor), the reaction temperature was 50 c, and the retention time was 4 minutes.
10% hydrochloric acid is pumped into the third mixer 18 with the components at a flow rate of 70mL/min, meanwhile, n-propanol is pumped into the third mixer 18 at a flow rate of 200mL/min, and the mixture is fed into an oil-water separator for liquid separation. Concentrating and desolventizing the organic phase to obtain the target compound hydroxypropyl pyrantriol (shown in formula I), wherein 3.27kg of the product is transparent oily matter with the purity of more than 99 percent and the yield: 85%, isomer ratio less than 1%.
Example 4
As shown in fig. 1, a synthetic method for preparing hydroxypropyl pyrantriol by continuous flow comprises the following steps:
9 kgD-xylose (a compound of formula II) was dissolved in 84L of ethanol, and stirred for 30 minutes, and D-xylose was completely dissolved to prepare a reaction solution A phase. 2.88kg of sodium hydroxide was dissolved in 30L of water to prepare a reaction liquid phase B. 7.2kg of acetylacetone was dissolved in 25L of ethanol to prepare a reaction solution C phase. Setting the flow rate of the phase A to 450mL/min by using plunger pumps respectively; the flow rate of the B-phase flow is 120mL/min; the flow rate of the C phase is 132mL/min; is pumped constantly into the first mixer 14 at a set flow rate and then into the first reactor 15 (microchannel reactor) with a reaction temperature set at 125℃and a retention time of 40 seconds.
3.2kg of NaBH 4 Suspended in 15L of water, pumped into the second mixer 16 by a slurry pump at a flow rate of 60mL/min, the temperature of the second mixer 16 was set to 50 ℃, the retention time was 110 seconds, and then entered into the second reactor 17 (baffle reactor), the reaction temperature was 50 ℃, and the retention time was 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 three times, merging organic phases, concentrating under reduced pressure to remove solvent, and obtaining a target compound hydroxypropyl pyrantriol (shown as a formula I), wherein 10kg of product is obtained, the product is transparent oily, the purity is more than 99%, and the yield is: 87%, isomer ratio less than 1%.
Example 5
As shown in fig. 1, a synthetic method for preparing hydroxypropyl pyrantriol by continuous flow comprises the following steps:
1.8-kgD-xylose (a compound of formula II) was dissolved in 16.8L of ethanol, and stirred for 30 minutes, D-xylose was completely dissolved to prepare a reaction solution A phase. 576g of sodium hydroxide was dissolved in 6L of water to prepare a reaction liquid phase B. 1.44kg of ethyl acetoacetate was dissolved in 5L of ethanol to prepare a reaction liquid phase C. Setting the flow rate of the phase A to 450mL/min by using plunger pumps respectively; the flow rate of the B-phase flow is 120mL/min; the flow rate of the C phase is 132mL/min; is pumped constantly into the first mixer 14 at a set flow rate and then into the first reactor 15, the reaction temperature is set at 125℃and the retention time is 40 seconds.
3.5kg NaBH (OAc) 3 Suspended in 3L of water, pumped into the second mixer 16 by a slurry pump at a flow rate of 60mL/min, the temperature of the second mixer 16 was set to 50 ℃, the retention time was 110 seconds, and then entered into the second reactor 17 (baffle reactor), the reaction temperature was 50 ℃, and the retention time was 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 three times, merging organic phases, concentrating under reduced pressure to remove solvent, and obtaining a target compound hydroxypropyl pyrantriol (shown as a formula I), wherein 1.9kg of product is obtained, and the product is transparent oily, the purity is more than 99%, and the yield is: 83%, isomer ratio less than 1%.
Comparative example 1
The procedure of example 1 of a method for synthesizing a glass color factor according to patent 202110383018.4 is carried out as follows: 500g of ethanol, 30g (0.2 mol) of xylose, 0.17g (2 mmol) of sodium bicarbonate and 26g (0.2 mol) of acetoacetate are sequentially added into a 1000mL reaction bottle, the temperature is raised to 60 ℃ by stirring, the reaction is continued for 1h, the reaction liquid is detected to basically disappear by TLC (GF 254 silica gel plate, developing agent is dichloromethane: methanol=4:1, and 20% sulfuric acid ethanol solution develops color). Then 11.3g (0.3 mol) of sodium borohydride is added dropwise at 0 ℃, after stirring evenly, 2N hydrochloric acid is slowly added dropwise after reacting for 24 hours at 50 ℃, the pH is adjusted to be neutral, ethyl acetate is used for extracting and separating liquid, an organic layer is collected, and the organic layer is dried by spinning, so that the vitrine is a caramel color oily substance, 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 hydroxypyrol prepared in comparative example 1, with relative retention time rt= 5.793min, is the desired target configuration product.
As shown in FIG. 3, which is a graphical representation of the hydroxypropyl pyrantriols obtained in example 2 and comparative example 1 of the present invention, the glassy cause obtained in comparative example 1 was caramel in color and the acetic acid taste was heavy, mainly due to the longer reaction time of comparative example 1. In contrast, the continuous flow synthesis method is adopted in the embodiment 2 of the invention, and the obtained glass color is colorless transparent solution, so that the acetic acid taste is very light and almost no sour taste is generated, which is a very important improvement for cosmetics. The physical product drawings of examples 3-5 are similar to those of example 1, and are not repeated here.
The synthesis method for preparing hydroxypropyl pyrantriol by continuous flow provided by the embodiment of the invention has the advantages of short reaction time, simple and convenient operation, high automation degree, low price and easy obtainment of reagents, good purity of the obtained product (the compound shown in the formula I), less impurities such as caramel, 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.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (7)
1. A synthetic method for preparing hydroxypropyl pyrantriol by continuous flow, which is characterized in that a continuous flow process is used, and intermediates obtained in the reaction process do not need to be separated, and the synthetic method comprises the following steps: under alkaline condition, xylose and acetylating agent are subjected to substitution reaction and reduction reaction in a continuous flow reactor, then are subjected to extraction, liquid separation and desolventizing after quenching, thus obtaining the product; the specific operation is as follows:
a first mixing step: pumping the xylose solution, the acylating reagent solution and the alkaline solution into a first mixer through a xylose solution feeding system, an acylating reagent solution feeding system and an alkaline solution feeding system respectively, and mixing to obtain a first mixture;
substitution reaction step: the first mixture enters a first reactor to carry out substitution reaction, and after a certain period of reaction, a second mixture is obtained;
a second mixing step: the second mixture enters a second mixer, a reducing agent is pumped into the second mixer, and after a certain period of reaction, a third mixture is obtained;
a reduction reaction step: the third mixture enters a second reactor for reduction reaction to obtain a fourth mixture;
quenching reaction steps: the fourth mixture enters a third mixer to carry out acid quenching reaction to obtain a fifth mixture;
separating: the fifth mixture enters an oil-water continuous separator for extraction, liquid separation and desolventizing, thus obtaining the oil-water continuous separator;
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; in the acylating reagent solution, the acylating reagent is acetylacetone and/or ethyl acetoacetate, and the solvent for dissolving the acylating 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 triacetate borohydride, 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 in 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;
in the first mixing step, the volume of the solvent in the xylose solution is 2-15 times of the volume of solute xylose, and the volume of the solvent used in the acylating reagent solution is 1-15 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): 1.0-2.0;
in the substitution reaction step, the reaction temperature is 80-180 ℃ and the reaction time is 30-300 seconds;
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.
2. The synthetic method for continuous flow preparation of hydroxypropyl pyrantriol according to claim 1, characterized in that in said first mixing step the solute of the xylose solution is xylose and the solvent is water, methanol, ethanol or n-butanol; in the acylating reagent solution, the solvent for dissolving the acylating 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 for dissolving or suspending the reducing agent is water, methanol, ethanol or n-butanol;
in the quenching reaction step, the aqueous acid solution used in the quenching reaction is aqueous hydrochloric acid solution;
in the separation step, the organic phase used for extraction is n-butanol.
3. The synthetic method for continuous flow preparation of hydroxypropyl pyrantriol according to claim 1, characterized in that in said first mixing step the volume of solvent in said xylose solution is 10-12 times the volume of solute xylose; in the acylating reagent solution, the volume of the solvent is 3 times of the volume of the acylating 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 substitution reaction step, 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 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.
4. The synthetic method for continuous flow preparation of hydroxypropyl pyrantriol according to claim 1, wherein said first mixer, said second mixer and said third mixer are all microchannel reactors, Y-mixers, T-mixers or three-way mixers;
the first reactor and the second reactor are microchannel reactors, pipeline reactors, silicon carbide cluster reactors or baffle plate reactors;
the oil-water continuous separator is an oil-water separator; alternatively, the continuous oil-water separation system comprises a distiller and an extractor.
5. A synthesis system for continuous flow preparation of hydroxypropyl pyrantriol, characterized in that it is used in the synthesis process according to any one of claims 1-4, comprising a feed system, a first mixer, a first reactor, a second mixer, a second reactor, a third mixer and an oil-water continuous separator, in series in this order; the feeding system comprises a xylose solution feeding system, an acylating reagent solution feeding system and an alkaline solution feeding system, wherein the xylose solution feeding system, the acylating reagent solution feeding system and the alkaline solution feeding system are respectively connected with the first mixer.
6. The synthetic system for continuous flow preparation of hydroxypropyl pyrantriol according to claim 5, wherein said oil-water continuous separator is an oil-water separator; alternatively, the continuous oil-water separation system comprises a distiller and an extractor.
7. The synthetic system for continuous flow preparation of hydroxypropyl pyrantriol according to claim 5, wherein said first mixer, said second mixer and said third mixer are all microchannel reactors, Y-mixers, T-mixers or three-way mixers;
the first reactor and the second reactor are microchannel reactors, pipeline reactors, silicon carbide cluster reactors or baffle plate reactors.
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