CN115340465B - Synthetic method of voglibose - Google Patents
Synthetic method of voglibose Download PDFInfo
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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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Abstract
The invention provides a method for synthesizing voglibose, belonging to the field of voglibose synthesis. The synthesis method of voglibose comprises the following steps: preparing a first intermediate, preparing a second intermediate and preparing voglibose. The synthesis method of the voglibose has mild reaction conditions, effectively avoids the use of raw materials such as tributyl tin hydride, iron powder, zinc powder and the like, has good safety of the raw materials, is easy to treat reaction waste liquid, and effectively reduces the production and environmental-protection related cost; the purity of the prepared voglibose is 99.85-99.98%, and the comprehensive yield is 64.1-67.5%.
Description
Technical Field
The invention relates to the field of voglibose synthesis, in particular to a synthetic method of voglibose.
Background
Voglibose was first developed by Takeda, japan in 1994, and korea in 1998, and is used for treating postprandial blood glucose elevation in diabetic patients. The voglibose is used for delaying the decomposition of disaccharide (starch is hydrolyzed into disaccharide under the action of amylase) into monosaccharide under the action of alpha-glucosidase by inhibiting alpha-glucosidase, and delaying the absorption speed of glucose and fructose, thereby reducing postprandial blood sugar.
In the therapeutic effect, the action intensity of voglibose is 190-270 times stronger than that of acarbose which is a similar product, and the voglibose has no adverse effect on a-glycosidase in the digestive tract of a patient. Meanwhile, the voglibose has low side effect, generally does not have hypoglycemia, has only abdominal distension and increased exhaust, and has good tolerance of patients.
US4898986A discloses a myosugar derivative, a process for its production and use, which produces voglibose by a 7-step reaction. In the technical scheme, in order to ensure good reaction effect, the reaction is carried out under extremely low temperature (about minus 50 ℃), the reaction conditions are harsh, the requirements on reaction devices are high, and the production energy consumption is high; meanwhile, in the process of preparing (2R, 3S,4S, 5S) -2,3, 4-tri (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexan-1-one from (3S, 4S,5S, 6R) -4,5, 6-tri (phenoxy) 3- [ (phenoxy) methyl ] -2,3, 4-tri (phenoxy) -5-hydroxycyclohexan-1-one, virulent tributyltin hydride needs to be adopted, and during the transportation, storage, feeding and cleaning processes, the toxic tributyltin hydride is harmful to the bodies of workers, the control cost is high, and the requirements of large-scale industrial production are not met.
Meanwhile, in the prior art, in the process of preparing (2R, 3S,4S, 5S) -2,3, 4-tris (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexan-1-one from (3S, 4S,5S, 6R) -4,5, 6-tris (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one, metal powder such as iron powder and zinc powder is used in the reaction process. However, in order to ensure a relatively ideal reaction effect, a large amount of metal powder such as iron powder, zinc powder and the like is required to be added; and after the reaction is finished, the reaction waste liquid is difficult to treat, the environmental friendliness is poor, and the environmental-friendly operation cost is huge.
Thus, a method for synthesizing voglibose, which can effectively catalyze the reaction process for preparing (2R, 3S,4S, 5S) -2,3, 4-tris (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexan-1-one from (3S, 4S, 5S) -4, 5-tris (phenoxy) methyl ] -4,5, 6-tris (phenoxy) 3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one; compared with the prior art, the method has the advantages of mild reaction conditions, good raw material safety and easy treatment of reaction waste liquid; meanwhile, the purity and yield index of the prepared voglibose are further improved, and the method has important significance.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a synthetic method of voglibose, which can effectively catalyze the reaction process of preparing (2R, 3S,4S, 5S) -2,3, 4-tris (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexane-1-one from (3S, 4S, 5S) -4,5, 6-tris (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexane-1-one; compared with the prior art, the method has the advantages of mild conditions, good raw material safety and easy treatment of reaction waste liquid; meanwhile, the purity and yield index of the prepared voglibose can be further improved.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a synthetic method of voglibose comprises the following steps: preparing a first intermediate, preparing a second intermediate and preparing voglibose.
The method for preparing the first intermediate comprises the steps of putting 154g-173g of ammonium carbonate and 105 g-130 g of reducing agent into 530 g-560 g of acetonitrile solution, uniformly stirring, heating to 30-35 ℃, and preserving heat; then, under the condition of stirring, 2000-2200mL of the first solution is dripped at the dripping speed of 8-10g/min; after the dropwise addition of the first solution is finished, continuously preserving the heat for 2-3h; filtering to obtain filtrate, and evaporating to dryness under reduced pressure at 45-50 deg.C in vacuum environment; extracting with 1300-1500mL ethyl acetate and 900-1000mL hydrochloric acid, washing with 900-1000mL saturated saline solution, drying with anhydrous magnesium sulfate, vacuum filtering, and evaporating at 40-45 deg.C under reduced pressure; then putting into 500-600mL of n-hexane, refluxing for 30-50min, cooling to 0-3 ℃, standing until no solid is separated out, filtering out solid substances, placing in a vacuum environment, and drying at 45-55 ℃ until the weight is unchanged to prepare a first intermediate, namely compound II, (2R, 3S,4S, 5S) -2,3, 4-tri (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexane-1-one);
the water content of the acetonitrile solution is 2.5-3%;
the first solution was a solution of compound I in acetonitrile, i.e. (3s, 4s,5s, 6r) -4,5, 6-tris (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one in acetonitrile. In the first solution, the concentration of the compound I is 5.5g/100mL;
the concentration of the hydrochloric acid is 1.8-2mol/L.
The reducing agent is prepared by the following method: modification and loading;
the modification method comprises the steps of putting a predetermined amount of activated carbon into a modification solution with the volume 15-25 times of that of the modification solution, heating to 80-90 ℃ under the stirring condition of 70-100rpm, preserving heat, continuing stirring for 2-4 hours, and filtering out the activated carbon; washing activated carbon with sufficient deionized water to neutrality, then placing the activated carbon in a vacuum environment, and drying the activated carbon at the temperature of 60-70 ℃ until the weight of the activated carbon is unchanged to prepare a modified carrier;
the activated carbon is shell activated carbon, the particle size is 300-400 mu m, and the aperture is 3-6nm;
the modified liquid is mixed acid of hydrochloric acid and phosphoric acid. In the modified liquid, the concentration of hydrochloric acid is 8-10wt%, the concentration of phosphoric acid is 4-7wt%, and the balance is deionized water.
The loading method comprises the steps of putting the modified carrier into negative carrier liquid with the volume 5-8 times of that of the modified carrier, heating to 35-40 ℃ under the stirring condition, preserving the temperature, continuing stirring for 5-8 hours, and filtering out solids; then putting the solid into a sodium borohydride solution with the concentration of 5-7wt%, heating to 25-35 ℃ under the condition of nitrogen atmosphere, and preserving heat for 1-2 hours; filtering and vacuum drying until the weight is unchanged to prepare a reducing agent;
the negative carrier liquid is prepared by mixing NiCl with a predetermined amount 2 ·6H 2 O、Cu(NO 3 ) 2 ·3H 2 Adding O and polyethylene glycol 400 into anhydrous ethanol, stirring for 10-30min, adjusting pH to 3-4 with dilute hydrochloric acid, and stirring to dissolve completely;
in the negative carrier liquid, cu 2+ Ion concentration of 8-10g/L, ni 2+ The ion concentration is 5-7g/L;
in the negative carrier liquid, the weight part ratio of polyethylene glycol 400 to absolute ethyl alcohol is 2-3;
the sodium borohydride and NiCl 2 ·6H 2 The molar ratio of O is 5-7.
The method for preparing the second intermediate comprises the steps of putting 89.5-97.2g of the compound II and 43.7-54.7g of 2-amino-1, 3-propanediol into 1200-1500mL of methanol, stirring and dissolving, heating to 30-35 ℃, preserving heat and stirring for 20-40min; then 28.3-34.6g of sodium cyanoborohydride and 5.7-9.5g of sodium borohydride are added, and the mixture is kept warm and stirred for 22-28h; then concentrating under reduced pressure to 30-35% of the original volume, adding 800-1000mL of deionized water, stirring uniformly, and then dropwise adding hydrochloric acid with the concentration of 1mol/L until no bubbles emerge; then extracting with 8000-9500mL ethyl acetate, washing with 4000-5000mL hydrochloric acid with the concentration of 1mol/L, washing with 4000-5000mL saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a second intermediate, namely compound III, (1S, 2S,3R,4S, 5S) -2,3, 4-tri (phenoxy) -1- [ (phenoxy) methyl ] -5- [ bis (hydroxymethyl) amino ] cyclohexan-1-ol.
The method for preparing the voglibose comprises the steps of adding 61.3-72.1g of the compound III and 100-180mL of formic acid into 3000-4000mL of methanol, stirring uniformly, continuing adding 15-20g of Raney nickel catalyst, and then introducing H 2 Reacting for 16-20h at the temperature of 35-40 ℃; then adding triethylamine to adjust the pH value to be neutral, and filtering to obtain filtrate; then decompressing and concentrating to 25-35% of the original volume, then adding 2000-3000mL of deionized water, stirring uniformly, extracting with 8000-9000mL of dichloromethane, and freeze-drying the water phase to obtain the voglibose.
Compared with the prior art, the invention has the following beneficial effects:
(1) The synthesis method of voglibose comprises the steps of setting a specific reducing agent in the process of preparing a first intermediate; in the preparation process of the reducing agent, the active carbon is treated by adopting the specific modification liquid, so that the porous structure of the active carbon is more stable, the circulation of substances is facilitated, and the catalytic activity of the reducing agent is improved; at the same time, by adopting NiCl containing specific active component 2 ·6H 2 O、Cu(NO 3 ) 2 ·3H 2 Treating the modified carrier by using O load liquid; the catalytic performance of the reducing agent on the preparation of the first intermediate can be effectively improved, the purity and the yield of the prepared first intermediate are effectively improved, the smooth proceeding of the subsequent reaction is effectively ensured, and the purity index of the final product voglibose is ensured; in the synthesis method of voglibose, the purity of the prepared first intermediate is 98.27-98.74%, and the yield is 92.7-94.4%。
(2) According to the synthetic method of voglibose, the sodium cyanoborohydride and the sodium borohydride are used in a compounding manner in the process of preparing the second intermediate, and the two are synergistic, so that the purity and the yield of the second intermediate are further improved; the purity of the second intermediate is 97.81-98.36%, and the yield is 70.3-72.2%.
(3) The synthesis method of voglibose has mild reaction conditions, effectively avoids the use of virulent substances such as tributyl tin hydride, effectively avoids the use of high pollutants such as iron powder and zinc powder, has good raw material safety, is easy to treat reaction waste liquid, and effectively reduces the production and environmental-protection related cost.
(4) According to the synthesis method of voglibose, the purity of the prepared voglibose is 99.85-99.98%, and the comprehensive yield is 64.1-67.5%.
Drawings
FIG. 1 is a chemical reaction equation of the synthesis method of voglibose according to the present invention.
FIG. 2 is a liquid chromatogram of voglibose obtained in example 1.
FIG. 3 is a liquid chromatogram of voglibose obtained in example 2.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
Example 1
A synthetic method of voglibose comprises the following specific steps:
1. preparation of the first intermediate
154g of ammonium carbonate and 105g of reducing agent are put into 530g of acetonitrile solution, and after uniform stirring, the temperature is raised to 30 ℃ and heat preservation is carried out; then, under the condition of stirring, 2000mL of the first solution is dripped at the dripping speed of 8 g/min; after the first solution is dropwise added, continuously preserving the heat for 2 hours; filtering to obtain filtrate, and then evaporating to dryness under reduced pressure at 45 ℃ in a vacuum environment; then 1300mL of ethyl acetate and 900mL of hydrochloric acid are adopted for extraction, 900mL of saturated saline solution is used for water washing, after drying of anhydrous magnesium sulfate, suction filtration is carried out, and reduced pressure evaporation is carried out at the temperature of 40 ℃ in a vacuum environment; then the mixture is put into 500mL of normal hexane, refluxed for 30min, cooled to 0 ℃, kept stand until no solid is precipitated, solid matters are filtered out, the mixture is placed in a vacuum environment, and dried at 45 ℃ until the weight of the mixture is unchanged, so that 92.4g of a first intermediate, namely compound II, (2R, 3S,4S, 5S) -2,3, 4-tri (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexane-1-one) is prepared, the purity is 98.27%, and the yield is 92.7%.
Wherein the water content of the acetonitrile solution was 2.5%.
The first solution was a solution of compound I in acetonitrile, i.e. (3s, 4s,5s, 6r) -4,5, 6-tris (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one in acetonitrile. The concentration of compound I in the first solution was 5.5g/100mL.
The concentration of the hydrochloric acid is 1.8mol/L.
The reducing agent is prepared by the following method:
1) Modification of
Putting a predetermined amount of activated carbon into the 15-time volume of the modified solution, heating to 80 ℃ under the stirring condition of 70rpm, preserving heat, continuing stirring for 2 hours, and filtering out the activated carbon; and (3) washing the activated carbon by using sufficient deionized water until the activated carbon is neutral, then placing the activated carbon in a vacuum environment, and drying the activated carbon at 60 ℃ until the weight of the activated carbon is unchanged to prepare the modified carrier.
Wherein the activated carbon is nutshell activated carbon, the particle size is 300 mu m, and the pore diameter is 3nm.
The modified liquid is mixed acid of hydrochloric acid and phosphoric acid. In the modification solution, the concentration of hydrochloric acid is 8wt%, the concentration of phosphoric acid is 4wt%, and the balance is deionized water.
2) Load(s)
Adding the modified carrier into negative carrier liquid with the volume 5 times that of the carrier liquid, heating to 35 ℃ under the stirring condition, preserving the temperature, continuing stirring for 5 hours, and filtering out solids; then putting the solid into a sodium borohydride solution with the concentration of 5wt%, heating to 25 ℃ under the condition of nitrogen atmosphere, and preserving heat for 1h; filtering and vacuum drying until the weight is unchanged to prepare the reducing agent.
The negative carrier liquid is prepared by mixing NiCl with a predetermined amount 2 ·6H 2 O、Cu(NO 3 ) 2 ·3H 2 Adding O and polyethylene glycol 400 into anhydrous ethanol, stirring for 10min, adjusting pH to 3 with dilute hydrochloric acid, and stirring to dissolve completely.
In the negative carrier liquid, cu 2+ Ion concentration of 8g/L, ni 2+ The ion concentration was 5g/L.
In the negative carrier liquid, the weight part ratio of polyethylene glycol 400 to absolute ethyl alcohol is 2.
The sodium borohydride and NiCl 2 ·6H 2 The molar ratio of O is 5.
2. Preparation of the second intermediate
Adding 89.5g of compound II and 43.7g of 2-amino-1, 3-propanediol into 1200mL of methanol, stirring for dissolving, heating to 30 ℃, preserving heat and stirring for 20min; then 28.3g of sodium cyanoborohydride and 5.7g of sodium borohydride are added, and the mixture is kept under the temperature and stirred for 22 hours; then concentrating under reduced pressure to 30% of the original volume, adding 800mL of deionized water, stirring uniformly, and then dropwise adding hydrochloric acid with the concentration of 1mol/L until no bubbles emerge; then extracted with 8000mL of ethyl acetate, washed with 4000mL of hydrochloric acid at a concentration of 1mol/L, washed with 4000mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 70.3g of a second intermediate, compound III, (1S, 2S,3R,4S, 5S) -2,3, 4-tris (phenoxy) -1- [ (phenoxy) methyl ] -5- [ bis (hydroxymethyl) amino ] cyclohexan-1-ol, having a purity of 97.81% and a yield of 70.3%.
3. Preparation of voglibose
Adding 61.3g of compound III and 100mL of formic acid into 3000mL of methanol, stirring uniformly, adding 15g of Raney nickel catalyst, and introducing H 2 Reacting for 16 hours at the temperature of 35 ℃; then adding triethylamine to adjust the pH value to be neutral, and filtering to obtain filtrate; then concentrating under reduced pressure to 25% of the original volume, then adding 2000mL of deionized water, stirring uniformly, extracting with 8000mL of dichloromethane, and freeze-drying the water phase to obtain 24.4g of voglibose, namely a compound IV with the purity of 99.85% and the yield of 98.3%.
In example 1, the overall yield of voglibose was 64.1%.
Example 2
A synthetic method of voglibose specifically comprises the following steps:
1. preparation of the first intermediate
Putting 173.0g of ammonium carbonate and 130g of reducing agent into 560g of acetonitrile solution, uniformly stirring, heating to 35 ℃, and keeping the temperature; then 2200mL of the first solution is dripped at the dripping speed of 10g/min under the stirring condition; after the first solution is dropwise added, continuously preserving the heat for 3 hours; filtering to obtain filtrate, and then evaporating to dryness under reduced pressure at 50 ℃ in a vacuum environment; extracting with 1500mL ethyl acetate and 1000mL hydrochloric acid, washing with 1000mL saturated saline, drying with anhydrous magnesium sulfate, vacuum filtering, and evaporating at 45 deg.C under reduced pressure; then the mixture is put into 600mL of normal hexane, refluxed for 50min, cooled to 3 ℃, kept stand until no solid is precipitated, solid matters are filtered out, the mixture is placed in a vacuum environment, and dried at 55 ℃ until the weight of the mixture is unchanged, so that 103.0g of a first intermediate, namely compound II, (2R, 3S,4S, 5S) -2,3, 4-tri (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexane-1-one) is prepared, the purity is 98.74%, and the yield is 94.4%.
Wherein the water content of the acetonitrile solution was 3%.
The first solution was a solution of compound I in acetonitrile, i.e. (3s, 4s,5s, 6r) -4,5, 6-tris (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one in acetonitrile. The concentration of compound I in the first solution was 5.5g/100mL.
The concentration of the hydrochloric acid is 2mol/L.
The reducing agent is prepared by the following method:
1) Modification of
Putting a predetermined amount of activated carbon into the modified solution with the volume 25 times that of the modified solution, heating to 90 ℃ under the stirring condition of 100rpm, preserving the temperature, continuing stirring for 4 hours, and filtering out the activated carbon; and (3) washing the activated carbon by using sufficient deionized water until the activated carbon is neutral, then placing the activated carbon in a vacuum environment, and drying the activated carbon at 70 ℃ until the weight of the activated carbon is unchanged to prepare the modified carrier.
Wherein the activated carbon is husk activated carbon, the particle size is 400 mu m, and the pore diameter is 6nm.
The modified liquid is mixed acid of hydrochloric acid and phosphoric acid. In the modification solution, the concentration of hydrochloric acid is 10wt%, the concentration of phosphoric acid is 7wt%, and the balance is deionized water.
2) Load(s)
Adding the modified carrier into a negative carrier liquid with the volume 8 times that of the carrier liquid, heating to 40 ℃ under the stirring condition, preserving heat, continuing stirring for 8 hours, and filtering out solids; then putting the solid into a sodium borohydride solution with the concentration of 7wt%, heating to 35 ℃ under the condition of nitrogen atmosphere, and preserving heat for 2 hours; filtering and vacuum drying until the weight is unchanged to prepare the reducing agent.
The preparation method of the negative carrier liquid is that a predetermined amount of NiCl is added 2 ·6H 2 O、Cu(NO 3 ) 2 ·3H 2 Adding O and polyethylene glycol 400 into anhydrous ethanol, stirring for 30min, adjusting pH to 4 with dilute hydrochloric acid, and stirring to dissolve completely.
In the negative carrier liquid, cu 2+ Ion concentration of 10g/L, ni 2+ The ion concentration was 7g/L.
In the negative carrier liquid, the weight part ratio of the polyethylene glycol 400 to the absolute ethyl alcohol is 3.
The sodium borohydride and NiCl 2 ·6H 2 The molar ratio of O is 7.
2. Preparation of the second intermediate
Adding 97.2g of compound II and 54.7g of 2-amino-1, 3-propanediol into 1500mL of methanol, stirring and dissolving, heating to 35 ℃, preserving heat and stirring for 40min; then 34.6g of cyano sodium borohydride and 9.5g of sodium borohydride are added, and the mixture is kept under the temperature and stirred for 28 hours; then concentrating under reduced pressure to 35% of the original volume, adding 1000mL of deionized water, stirring uniformly, and then dropwise adding hydrochloric acid with the concentration of 1mol/L until no bubbles emerge; then, the mixture was extracted with 9500mL of ethyl acetate, washed with 5000mL of hydrochloric acid having a concentration of 1mol/L, washed with 5000mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 78.3g of a second intermediate, compound III, (1S, 2S,3R,4S, 5S) -2,3, 4-tris (phenoxy) -1- [ (phenoxy) methyl ] -5- [ bis (hydroxymethyl) amino ] cyclohexan-1-ol having a purity of 98.36% and a yield of 72.2%.
3. Preparation of voglibose
71.2g of Compound III and 180mL of formic acid were added to 4000mL of methanol and the mixture was stirredAfter homogenizing, 20g of Raney nickel catalyst is added continuously, and then H is introduced 2 Reacting for 20 hours at the temperature of 40 ℃; then adding triethylamine to adjust the pH value to be neutral, and filtering to obtain filtrate; then concentrating under reduced pressure to 35% of the original volume, then adding 3000mL of deionized water, stirring uniformly, extracting with 9000mL of dichloromethane, and freeze-drying the water phase to obtain 28.6g of voglibose, namely a compound IV with the purity of 99.98% and the yield of 99.0%.
In example 2, the overall yield of voglibose was 67.5%.
Comparative example 1
The technical solution of embodiment 2 is adopted, which is different in that: 1) In the step of preparing the first intermediate, in the step of preparing the reducing agent, the modification step is omitted; in the step of preparing the first intermediate in comparative example 1, 101.1g of the first intermediate (i.e., compound II) was obtained with a purity of 96.16% and a yield of 90.2%. 2) In the step of preparing the second intermediate, cyano sodium borohydride is adopted to replace sodium borohydride; in the step of preparing the second intermediate in comparative example 1, 77.1g of the second intermediate (i.e., compound III) was obtained with a purity of 97.06% and a yield of 70.1%.
Comparative example 2
The technical solution of embodiment 2 is adopted, which is different in that: in the step of preparing the first intermediate, in the step of preparing the reducing agent, the loading step is changed to: adding the modified carrier into negative carrier liquid with 6 times of volume, heating to 35-40 ℃ under the stirring condition, preserving heat, continuing stirring for 5-8h, and filtering out solids; vacuum drying until the weight is unchanged to prepare the reducing agent.
The preparation method of the negative carrier liquid comprises the steps of putting Fe powder and Cu powder into deionized water, and uniformly dispersing to obtain the negative carrier liquid. In the negative carrier liquid, the concentration of Cu powder is 9g/L, and the concentration of Fe powder is 6g/L.
In the first intermediate preparation step of comparative example 2, 103.2g of the first intermediate (i.e., compound II) was obtained with a purity of 92.31% and a yield of 88.5%.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A synthetic method of voglibose is characterized by comprising the following steps of: preparing a first intermediate, preparing a second intermediate and preparing voglibose;
the method for preparing the first intermediate comprises the steps of putting ammonium carbonate and a reducing agent into an acetonitrile solution, uniformly stirring, heating to 30-35 ℃, and preserving heat; then, under the condition of stirring, dropwise adding the first solution; after the dropwise addition of the first solution is finished, continuously preserving the heat for 2-3h; filtering to obtain filtrate, and evaporating to dryness at 45-50 deg.C under vacuum; then extracting with ethyl acetate and hydrochloric acid, washing with saturated saline water, drying with anhydrous magnesium sulfate, vacuum filtering, and evaporating to dryness at 40-45 deg.C under vacuum; then putting into normal hexane, refluxing for 30-50min, cooling to 0-3 ℃, standing until no solid is separated out, filtering out solid substances, placing in a vacuum environment, and drying at 45-55 ℃ until the weight is unchanged to prepare a first intermediate;
the first intermediate is (2R, 3S,4S, 5S) -2,3, 4-tris (phenoxy) -5- [ (phenoxy) methyl ] -5-hydroxycyclohexan-1-one;
the first solution is acetonitrile solution of compound I;
the compound I is (3S, 4S,5S, 6R) -4,5, 6-tri (phenoxy) -3- [ (phenoxy) methyl ] -2, 2-dichloro-3-hydroxycyclohexan-1-one;
the preparation method of the reducing agent comprises the following steps: modification and loading;
the modification method comprises the steps of putting activated carbon into modification liquid with the volume 15-25 times of that of the modified liquid, heating to 80-90 ℃ under the condition of stirring, preserving heat, continuing stirring for 2-4 hours, and filtering out the activated carbon; washing activated carbon with sufficient deionized water until the activated carbon is neutral, then placing the activated carbon in a vacuum environment, and drying the activated carbon at the temperature of 60-70 ℃ until the weight of the activated carbon is unchanged to prepare a modified carrier;
the activated carbon is shell activated carbon, the particle size is 300-400 mu m, and the aperture is 3-6nm;
in the modified solution, the concentration of hydrochloric acid is 8-10wt%, the concentration of phosphoric acid is 4-7wt%, and the balance is deionized water;
the loading method comprises the steps of putting the modified carrier into negative carrier liquid with the volume 5-8 times of that of the modified carrier, heating to 35-40 ℃ under the stirring condition, preserving the temperature, continuing stirring for 5-8 hours, and filtering out solids; then putting the solid into a sodium borohydride solution with the concentration of 5-7wt%, heating to 25-35 ℃ under the condition of nitrogen atmosphere, and preserving heat for 1-2 hours; filtering and vacuum drying until the weight is unchanged to prepare a reducing agent;
the negative carrier liquid is prepared by mixing NiCl with a predetermined amount 2 ·6H 2 O、Cu(NO 3 ) 2 ·3H 2 Adding O and polyethylene glycol 400 into anhydrous ethanol, stirring for 10-30min, adjusting pH to 3-4, and stirring to dissolve completely;
in the negative carrier liquid, cu 2+ Ion concentration of 8-10g/L, ni 2+ The ion concentration is 5-7g/L;
in the negative carrier liquid, the weight part ratio of polyethylene glycol 400 to absolute ethyl alcohol is 2-3;
the sodium borohydride and NiCl 2 ·6H 2 The molar ratio of O is 5-7;
the method for preparing the second intermediate comprises the steps of putting the first intermediate and 2-amino-1, 3-propylene glycol into methanol, stirring and dissolving, heating to 30-35 ℃, preserving heat and stirring for 20-40min; then adding sodium cyanoborohydride and sodium borohydride, and continuing to keep the temperature and stir for 22-28h; then decompressing and concentrating to 30-35% of the original volume, putting into deionized water, stirring evenly, and then dripping hydrochloric acid with the concentration of 1mol/L until no bubbles emerge; then extracting by using ethyl acetate, washing by using hydrochloric acid with the concentration of 1mol/L, washing by using a saturated sodium bicarbonate solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to prepare a second intermediate;
the second intermediate is (1S, 2S,3R,4S, 5S) -2,3, 4-tris (phenoxy) -1- [ (phenoxy) methyl ] -5- [ bis (hydroxymethyl) amino ] cyclohex-1-ol.
2. The method for synthesizing voglibose according to claim 1, wherein in the preparation of the first intermediate, the dropping rate of the first solution is 8 to 10g/min;
the water content of the acetonitrile solution is 2.5-3%;
in the first solution, the concentration of the compound I is 5.5g/100mL;
the concentration of the hydrochloric acid is 1.8-2mol/L.
3. The method for synthesizing voglibose according to claim 1, wherein in the preparation of the first intermediate, the ratio of ammonium carbonate, the reducing agent and the compound I in parts by weight is 154-173.
4. The method for synthesizing voglibose according to claim 1, wherein the ratio of parts by weight of the first intermediate, 2-amino-1, 3-propanediol, sodium cyanoborohydride and sodium borohydride in the preparation of the second intermediate is 89.5-97.2.
5. The method for synthesizing voglibose according to claim 1, wherein the method for preparing voglibose comprises the steps of adding the second intermediate and formic acid into methanol, stirring the mixture uniformly, adding the Raney nickel catalyst continuously, and introducing H 2 Reacting for 16-20h at the temperature of 35-40 ℃ in a heat preservation way; adding triethylamine to adjust the pH value to be neutral, and filtering to obtain filtrate; then concentrating under reduced pressure to 25-35% of the original volume, then adding deionized water, stirring uniformly, extracting by adopting dichloromethane, and freeze-drying the water phase to obtain the voglibose.
6. The synthesis method of voglibose according to claim 5, wherein the ratio of parts by weight of the second intermediate to parts by weight of formic acid in the preparation of voglibose is 61.3-71.2.
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|---|---|---|---|---|
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
| WO2005049547A1 (en) * | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for the preparation of 1,2,3,4-cyclohexanetetrol derivatives |
| CN101007771A (en) * | 2007-01-26 | 2007-08-01 | 深圳市药兴生物科技开发有限公司 | Voglibose semi-hydrated crystal, its preparation method and its uses in medicament formulation |
| CN101279925A (en) * | 2008-05-30 | 2008-10-08 | 雷云 | Tetrabenzyl voglibose, preparation and application thereof |
| CN113214094A (en) * | 2021-04-26 | 2021-08-06 | 潍坊天福化学科技有限公司 | Synthetic method of voglibose |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
| WO2005049547A1 (en) * | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for the preparation of 1,2,3,4-cyclohexanetetrol derivatives |
| CN101007771A (en) * | 2007-01-26 | 2007-08-01 | 深圳市药兴生物科技开发有限公司 | Voglibose semi-hydrated crystal, its preparation method and its uses in medicament formulation |
| CN101279925A (en) * | 2008-05-30 | 2008-10-08 | 雷云 | Tetrabenzyl voglibose, preparation and application thereof |
| CN113214094A (en) * | 2021-04-26 | 2021-08-06 | 潍坊天福化学科技有限公司 | Synthetic method of voglibose |
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