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CN113214094A - Synthetic method of voglibose - Google Patents

Synthetic method of voglibose Download PDF

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CN113214094A
CN113214094A CN202110452158.2A CN202110452158A CN113214094A CN 113214094 A CN113214094 A CN 113214094A CN 202110452158 A CN202110452158 A CN 202110452158A CN 113214094 A CN113214094 A CN 113214094A
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compound
reaction
voglibose
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崔文文
杜金龙
袁西强
论宗文
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Weifang Tianfu Chemical Technology Co ltd
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Weifang Tianfu Chemical Technology Co ltd
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Abstract

The invention provides a synthesis method of voglibose, which solves the technical problems that in the existing synthesis method of voglibose, raw materials are difficult to obtain and have high price, the input is large and the yield is low, and the synthesis method is not suitable for industrial production. The method can be widely applied to the technical field of voglibose synthesis methods.

Description

Synthetic method of voglibose
Technical Field
The application belongs to the technical field of voglibose synthesis methods, and particularly relates to a voglibose synthesis method.
Background
The incidence of Diabetes Mellitus (DM) in China is increasing year by year. Currently, there are several main classes of drugs for the treatment of DM: alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, prandial blood sugar regulators, vanadium compounds, insulin, lipid-regulating therapeutic agents, NO synthase inhibitors, beta 3-receptor agonists, and the like. The alpha-glucosidase inhibitor is used as a new generation of hypoglycemic drugs, reduces and delays the absorption of carbohydrates in intestinal tracts and reduces postprandial hyperglycemia by inhibiting the alpha-glucosidase, and effectively treats type II DM. The influence on liver and kidney functions is small. The alpha-glucosidase inhibitors which are already on the market mainly comprise voglibose, acarbose, miglitol and the like.
At present, the preparation process of voglibose is complex, the market price is high, and therefore, the development of the high-efficiency synthesis method of voglibose is of great significance.
Disclosure of Invention
The invention aims to solve the defects of the background technology and provides a synthesis method of voglibose, which comprises eleven reaction steps, wherein a compound V is synthesized by taking glucose monohydrate and sodium acetate as raw materials, a compound VIII is prepared by utilizing the compound V through an addition reaction, a ring opening reaction and a aldol condensation reaction, and the voglibose is obtained by carrying out amination reduction on the compound VIII. The method has the advantages of cheap and easily-obtained reaction raw materials, mild reaction conditions, simple operation of the post-treatment process, obvious saving of the production cost, improvement of economic benefits, low cost, suitability for industrial production and accordance with the currently pursued environmental protection and energy conservation concepts.
Therefore, the invention provides a synthetic method of voglibose, which specifically comprises the following steps:
step 1: taking glucose monohydrate and sodium acetate as raw materials, and adding acetic anhydride to prepare a compound I, wherein the structural formula is as follows:
Figure BDA0003039211180000021
；
step 2: mixing the compound I prepared in the step (1) with p-methylthiophenol, stirring and dropwise adding Lewis acid (BF 3. Et2O) to perform glycosylation reaction to prepare a compound II, wherein the structural formula is shown in the specification;
Figure BDA0003039211180000022
；
and step 3: and (3) mixing the compound II prepared in the step (2) with sodium methoxide, reacting to obtain an intermediate, and then adding sodium hydride and benzyl bromide to obtain a compound III, wherein the structural formula is as follows:
Figure BDA0003039211180000023
；
and 4, step 4: adding N-bromosuccinimide (NBS) into the compound III prepared in the step 3 in batches, and carrying out oxidation reaction to obtain a compound IV, wherein the structural formula is as follows:
Figure BDA0003039211180000024
；
and 5: adding the compound IV prepared in the step 4 into dimethyl sulfoxide, dropwise adding acetic anhydride, and carrying out oxidation reaction to obtain a compound V, wherein the structural formula is as follows:
Figure BDA0003039211180000031
；
step 6: dropwise adding Lithium Diisopropylamide (LDA) solution into the compound V prepared in the step 5 to perform addition reaction to prepare a compound VI, wherein the structural formula is as follows:
Figure BDA0003039211180000032
；
and 7: adding sodium borohydride into the compound V prepared in the step 6 in batches, and carrying out a ring-opening reaction to prepare a compound VII with the structural formula as follows:
Figure BDA0003039211180000033
；
and 8: adding dimethyl sulfoxide and trifluoroacetic anhydride into an organic solvent, then adding the compound VII and triethylamine prepared in the step 7, and carrying out aldol condensation reaction to obtain a compound VIII, wherein the structural formula is as follows:
Figure BDA0003039211180000034
；
and step 9: mixing the compound VIII prepared in the step 8 with Azobisisobutyronitrile (AIBN) and tributyltin, heating under protective gas for reaction, and then adding ethyl acetate to prepare a compound IX, wherein the structural formula is as follows:
Figure BDA0003039211180000041
；
step 10: reacting the compound IX prepared in the step 9 with 2-amino-1, 3-propanediol and methanol, and then adding a reducing agent sodium cyanoborohydride to prepare a compound X, wherein the structural formula is as follows:
Figure BDA0003039211180000042
；
step 11: adding the compound X prepared in the step 10 and 10% Pd/C of a catalyst into a methanol-formic acid solvent system, introducing hydrogen, and carrying out reduction reaction to prepare voglibose, wherein the structural formula is as follows:
Figure BDA0003039211180000043
；
preferably, in the step 1, the reaction temperature is 100-;
the reaction temperature of the step 2 is 20-40 ℃, and the reaction time is 4-8 h;
the reaction temperature of the step 3 is 10-20 ℃, and the reaction time is 0.5-1 h;
the reaction temperature of the step 4 is 20-40 ℃, and the reaction time is 0.5-2 h;
the reaction temperature of the step 5 is 15-25 ℃, and the reaction time is 10-25 h;
the reaction temperature of the step 6 is-50 to-80 ℃, and the reaction time is 1 to 2 hours;
the reaction temperature of the step 7 is 20-40 ℃, and the reaction time is 4-8 h;
the reaction temperature of the step 8 is-50 to-80 ℃, and the reaction time is 1 to 3 hours;
the reaction temperature of the step 9 is 90-110 ℃, and the reaction time is 1-2 h;
the reaction temperature of the step 10 is 20-40 ℃, and the reaction time is 40-50 h;
the reaction temperature of the step 11 is 30-50 ℃, and the reaction time is 16-20 h.
Preferably, in step 1, the molar ratio of the reactant glucose monohydrate to acetic anhydride is 1: (5-6);
in the step 2, the molar ratio of the compound I to the p-methylthiophenol is 1 (1-1.5);
in the step 3, the molar ratio of the compound II to sodium methoxide is 1 (4-5), the molar ratio of the compound II to sodium hydride is 1:5-7, and the molar ratio of the compound II to benzyl bromide is 1 (5-6);
in step 4, the molar ratio of the compound III to the N-bromosuccinimide is 1: (3-4);
in the step 5, the molar ratio of the compound IV to the acetic anhydride is 1 (1-1.5);
in step 7, the molar ratio of the compound VI to the sodium borohydride is 1: (1-2);
in step 9, the molar ratio of the compound VIII to the Azobisisobutyronitrile (AIBN) and the tributyltin is 1 (0.1-0.5) to (3-4).
Preferably, the LDA solution in step 6 is prepared from diisopropylamine and butyllithium.
Preferably, the reaction conditions of diisopropylamine and butyllithium are: the reaction temperature is-5 ℃ to-1 ℃, the reaction time is 1-2h, and the molar ratio of diisopropylamine to butyllithium is 1: (1-2).
Preferably, in step 6, column chromatography is required after the ring-opening reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (6-10): 1.
preferably, in step 8, column chromatography is required after the aldol condensation reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (6-12): 1.
preferably, in step 9, tributyltin is prepared by reacting tributyltin chloride with lithium aluminum hydride.
Preferably, the reaction conditions of tributyltin chloride and lithium aluminum hydride are as follows: the reaction temperature is 20-40 ℃, the reaction time is 2-4h, and the molar ratio of tributyltin chloride to lithium aluminum hydride is 1 (3-4).
Preferably, in step 9, column chromatography is required after the reduction reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (3-8): 1.
the invention has the beneficial effects that:
(1) the invention provides a preparation method of voglibose, which comprises eleven reaction steps, synthesizing a compound V by taking glucose monohydrate and sodium acetate as raw materials, preparing a compound VIII by utilizing the compound V through addition reaction, ring-opening reaction and aldol condensation reaction, and obtaining the voglibose through amination reduction of the compound VIII. The method has the advantages of cheap and easily-obtained reaction raw materials, mild reaction conditions, simple operation of the post-treatment process, obvious saving of the production cost, improvement of economic benefits, low cost, suitability for industrial production and accordance with the currently pursued environmental protection and energy conservation concepts.
(2) In step 2 of the present invention, compound I is reacted with p-toluenesulfonyl in glycosidation with lewis acid (BF3 · Et2O) as a catalyst, and then recrystallized from absolute ethanol-cyclohexane to obtain compound II in high yield of 95.8%. In the step 3-4, removing acetyl protecting group in the compound II by using sodium methoxide, and then obtaining a benzyl protected compound IV with the exposed hydroxyl at the anomeric position through benzyl protection and glucoside desulfurization. In the step 5, a cheap and easily-obtained dimethyl sulfoxide-acetic anhydride system is adopted to oxidize the hydroxyl of the compound IV into carbonyl to obtain an intermediate compound IV, the reaction yield of the step is improved to more than 98%, and the reaction condition is very mild and is insensitive to air and water vapor. The method adopts the paratoluensulfide to protect the anomeric position of the glucose, not only can avoid unpleasant taste, but also the product is solid and can be purified by a recrystallization method, thereby greatly improving the reaction yield. The total yield of the five-step reaction is up to 85.1%, and the method is simple, convenient and easy to operate, free of column chromatography purification, low in cost and environment-friendly.
(3) In step 6 of the invention, the reaction yield is improved by limiting the reaction time, and the yield is close to 100%. In step 7 of the invention, compound VI is reduced to straight-chain alcohol by sodium borohydride to obtain ring-opening product compound VII which is an epimeric mixture. In step 8 of the invention, two free hydroxyls are oxidized into ketone by DMSO/TFAA, then organic base triethylamine is added to carry out intramolecular aldol condensation reaction to form a compound VIII, and the yield of the three-step reaction is up to 76.7%.
(4) In step 10, the method provided by the invention uses sodium cyanoborohydride as a reducing agent, obtains the required unique alpha-configuration product with 73.1% yield and high stereoselectivity, avoids a complex separation process, and greatly improves the production efficiency. In the step 11 of the invention, the methanol-formic acid solvent system has better dissolving capacity to raw materials and products, can shorten the reaction time and improve the reaction yield, and uses 10 percent Pd-C as a catalyst to replace the original Pd-black, thereby further improving the reaction yield. In the post-treatment process, the invention can meet the purity requirement only by neutralizing formic acid, filtering and washing with DCM, thereby greatly improving the efficiency and reducing the reaction cost.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
The synthetic route of the reaction is as follows:
Figure BDA0003039211180000071
example 1
Step 1: synthesis of peracetylated glucose
After 19.8g of glucose monohydrate and 15g of sodium acetate were mixed and ground, they were transferred to a three-necked flask, and 120mL of acetic anhydride (Ac) was added2O), and reacting for 2h at 120 ℃ under stirring. Pouring into 300g of ice water, stirring vigorously to separate out a solid, and standing in an ice bath for 2 hours. And (3) carrying out suction filtration, washing a filter cake by using distilled water, and recrystallizing by using absolute ethyl alcohol-cyclohexane to obtain 35.5g of fully acetylated glucose with the yield of 71.3%.
In this step, different reaction conditions were tried. Such as: the raw material ratio (glucose monohydrate: acetic anhydride ═ 1:5 or 1: 6), the reaction temperature (100 ℃, 140 ℃) and the reaction time (1h, 3h and 5h) are adopted, and the yield of the obtained product is 68-73%.
Step 2: synthesis of 2,3,4, 6-tetra-O-acetyl-beta-D-glucose bensosulfaside
150mL of dichloromethane was added to a bottle in the shape of eggplant, 20g of the fully acetylated glucose prepared in step 1 and 9.5g of p-methylthiophenol were added to dichloromethane, cooled in an ice water bath, and 13 g of the mixture was slowly added dropwise with stirringmL of Lewis acid (BF)3Et2O), after completion of the dropwise addition, reacted at 25 ℃ for 5 h. Diluted with 50mL of distilled water and solid sodium bicarbonate was added slowly to pH 7. After diluting with 500mL of dichloromethane, the mixture was washed with 100mL of saturated sodium bicarbonate solution and 100mL of saturated saline solution, and dried over anhydrous sodium sulfate; vacuum concentrating, and recrystallizing the residue with anhydrous ethanol-cyclohexane to obtain 21.9g white needle crystal product with yield of 95.8%.
In this step, different reaction conditions were tried. Such as: the raw material ratio (total acetylated glucose: p-methylthiophenol ═ 1: 1 or 1: 5), the reaction temperature (20 ℃, 40 ℃) and the reaction time (4h, 6h and 8h) are respectively adopted, and the yield of the obtained product is 93.85-96.11%.
And step 3: synthesis of 2,3,4, 6-tetra-O-benzyl-beta-D-glucose bensosulfan
200mL of methanol/dichloromethane solution was added to a bottle in the form of eggplant, 17.6g of 2,3,4, 6-tetra-O-acetyl-. beta. -D-glucosylbenzenesulfenthiin prepared in step 2 was added to the methanol/dichloromethane solution, and 50mg of sodium methoxide was added thereto with stirring to react at 20 ℃ for 0.5 hour. Adding cation exchange resin for neutralization and filtration, decompressing and concentrating the filtrate to obtain light yellow liquid, and directly carrying out the next reaction.
The pale yellow liquid was dissolved in 200mL of DMF, cooled in an ice-water bath, and 10.4g of NaH was added in portions with stirring and reacted at 20 ℃ for 0.5 h. And cooling in an ice water bath, dropwise adding 28.5mL of benzyl bromide, and reacting for 6 h. The reaction was terminated by slowly adding 50mL of distilled water until a large amount of bubbles appeared. The pH was adjusted to < 1 with 1mol/L hydrochloric acid, a large number of yellow particles appeared and left to stand at-18 ℃ for 3 h. Filtering, washing filter cake with cold water, drying to obtain 25.2g yellow solid product with 99.9% yield.
In this step, different reaction conditions were tried. Such as: the raw material ratio (2,3,4, 6-tetra-O-acetyl-beta-D-glucose phenyl methyl glucoside: sodium methoxide: sodium hydride: benzyl bromide ═ 1: 4: 5:6 or 1: 5:7:6), the reaction temperature (10 ℃, 15 ℃) and the reaction time (06h, 0.8h and 1h) are respectively adopted, and the yield of the obtained product is 99.11-99.9%.
And 4, step 4: synthesis of 2,3,4, 6-tetra-O-benzyl-glucose
19.4g of 2,3,4, 6-tetra-O-benzyl-beta-D-glucosylbenzenesulfenthionin prepared in step 3 was added to 500mL of acetone, and 18.7g N-bromosuccinimide (NBS) was added in portions with stirring and reacted at 25 ℃ for 0.5h after the addition. Most of the acetone was distilled off under reduced pressure to precipitate a white solid, which was diluted with 200mL of 1mol/L hydrochloric acid and allowed to stand at-18 ℃ for 3 hours. And (3) carrying out suction filtration, washing a filter cake by using cold absolute ethyl alcohol, and recrystallizing by using absolute ethyl alcohol-cyclohexane to obtain 15.6g of a white flocculent solid product with the yield of 96.6%.
In this step, different reaction conditions were tried. Such as: the raw material ratio (2,3,4, 6-tetra-O-benzyl-beta-D-glucosylbenzenesulfenthioside: N-bromosuccinimide) ═ 1:3 or 1: 4) the reaction temperature (20 ℃, 40 ℃) and the reaction time (1h, 1.5h and 2h) are adopted, and the yield of the obtained product is 94.85-96.46%.
And 5: synthesis of 2,3,4, 6-tetra-O-benzyl-glucolactone
5.4g of 2,3,4, 6-tetra-O-benzyl-glucose prepared in step 4 was added to 40mL of dimethyl sulfoxide, and 20mL of acetic anhydride (Ac) was added dropwise with stirring2O), reacting at 25 ℃ for 12h, and adding saturated sodium bicarbonate to neutralize. 100mL of methylene chloride was added, and the mixture was washed with 50mL of water and 50mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 56.8g of a yellow oily liquid product with a yield of 98.5%.
In this step, different reaction conditions were tried. Such as: raw material ratio (2,3,4, 6-tetra-O-benzyl-glucose: acetic anhydride) ═ 1: 1 or 1: 1.5), the reaction temperature (15 ℃, 20 ℃) and the reaction time (10h, 15h, 20h and 25h), the yield of the obtained product is 96.02-98.74%.
Step 6: synthesis of (2R,3R,4S,5R,6R) -3,4, 5-tri-benzyl-6-benzyloxymethyl-2-dichloromethyl-tetrahydro-2H-pyran-2-ol
Adding 850 mu L of diisopropylamine into 6mL of dry tetrahydrofuran, cooling the mixture to the temperature of minus 5 to minus 1 ℃ in an ice salt bath, dropwise adding 2.4mL of butyl lithium n-hexane solution under stirring, and reacting for 1 to 2 hours after dropwise adding is finished to obtain the LDA solution.
Adding 1.6g of 2,3,4, 6-tetra-O-benzyl-gluconolactone prepared in the step 5 into 15mL of dichloromethane, cooling to-70 ℃, dropwise adding LDA solution under stirring, and reacting for 1h at-70 ℃ after dropwise adding. The reaction was terminated by adding 20mL of 1mol/L hydrochloric acid, and diluted with 200mL of dichloromethane, followed by 60mL of 1mol/L hydrochloric acid, 60mL of saturated sodium bicarbonate solution, and 40mL of saturated saline solution, followed by drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain a pale yellow oily liquid, which was purified by silica gel column chromatography (gradient eluent: V (petroleum ether): V (ethyl acetate): 10: 1-6: 1) to obtain 1.84g of a pale yellow oily liquid product with a yield of 99.6%.
In this step, different reaction conditions were tried. Such as: diisopropylamine: butyl lithium ═ 1: 1 or 1:2, 2,3,4, 6-tetra-O-benzyl-gluconolactone and LDA solution at (-50 deg.C, -60 deg.C, -80 deg.C) for 1.5h, 2h to obtain product with yield of 98.66-99.2%.
And 7: synthesis of (3R,4S,5R) -3,4,5, 7-tetra-benzyloxy-1, 1-dichloroheptane-2, 6-diol
1.84g of (2R,3R,4S,5R,6R) -3,4, 5-tri-benzyl-6-benzyloxymethyl-2-dichloromethyl-tetrahydro-2H-pyran-2-ol from step 6 was added to 20mL of dimethyl ether, 190mg of sodium borohydride was added in portions under cooling in an ice bath, and after the addition was completed, the mixture was reacted at 25 ℃ for 6 hours. Concentrated under reduced pressure, the residue was dispersed in 20mL of water, extracted with 100mL of ethyl acetate, and the combined extracts were washed with 30mL of 1mol/L hydrochloric acid, 30mL of a sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 1.74g of a pale yellow oily liquid product with a yield of 93.1%.
In this step, different reaction conditions were tried. Such as: feed ratio ((2R,3R,4S,5R,6R) -3,4, 5-tri-benzyl-6-benzyloxymethyl-2-dichloromethyl-tetrahydro-2H-pyran-2-ol: sodium borohydride) ═ 1: 1 or 1: 2) the reaction temperature (20 ℃, 40 ℃) and the reaction time (4h and 8h) are controlled, and the yield of the obtained product is 92.77-93.65%.
And 8: synthesis of (2R,3S,4S,5S) -4,5, 6-tris-benzyloxy-3-benzyloxymethyl-2, 2-di-chloro-3-hydroxycyclohexanone
Adding 1.2mL of dimethyl sulfoxide and 15mL of dichloromethane into a reaction bottle, stirring to mix, cooling to-70 ℃, dropwise adding 1.16mL of trifluoroacetic anhydride, and reacting for 0.5h after dropwise adding; 1.18g of (3R,4S,5R) -3,4,5, 7-tetra-benzyloxy-1, 1-dichloroheptane-2, 6-diol obtained in step 7 was added dropwise thereto, and the reaction was carried out for 1 hour after completion of the addition. Et3N, 2.3mL, was added and reacted for 15 min. Gradually raising the temperature to 0 ℃, adding 10mL of ice water, stirring for 15min, then adding 100mL of dichloromethane for dilution, washing with 30mL of 1mol/L hydrochloric acid, 40mL of saturated sodium bicarbonate solution and 40mL of saturated saline solution respectively, drying by anhydrous sodium sulfate, concentrating, and purifying the residue by column chromatography (gradient eluent: V (petroleum ether): V (ethyl acetate): 12: 1-6: 1) to obtain 1.02g of white solid product with the yield of 75.5%.
In this step, different reaction conditions were tried. Such as: the reaction temperature is (-50 ℃, 60 ℃ below zero, -80 ℃) and the reaction time is (2h and 3h), and the yield of the obtained product is 70.25-76.42%.
And step 9: synthesis of (2R,3S,4S,5S) -2,3, 4-tris-benzyloxy-5-benzyloxymethyl-5-hydroxycyclohexanone
Adding 1.5g of tributyltin chloride into 5mL of diethyl ether, cooling in an ice-water bath, adding 60mg of lithium aluminum hydride in batches under stirring, and reacting for 15min after the addition is finished; the temperature is raised to 25 ℃ and the reaction is carried out for 3 h. Adding a proper amount of ice water, and stirring until no obvious bubbles emerge. Then, 50mL of diethyl ether was added, and the mixture was washed with 50mL of ice water, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless clear transparent liquid, tributyltin (kept under Ar atmosphere for further use).
745.2mg of (2R,3S,4S,5S) -4,5, 6-tris-benzyloxy-3-benzyloxymethyl-2, 2-di-chloro-3-hydroxycyclohexanone from step 8 was added to 10mL of a toluene solution, and 40mg of Azobisisobutyronitrile (AIBN), 1.22g of tributyltin was added with stirring, and the mixture was heated to 100 ℃ under argon atmosphere and reacted for 1 hour. After cooling to room temperature, 50mL of ethyl acetate was added, and the mixture was washed with 40mL of 1mol/L hydrochloric acid and 40mL of saturated sodium bicarbonate solution, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (gradient eluent V (petroleum ether): V (ethyl acetate): 8:1 to 3:1) to obtain 571.7mg of a white solid product with a yield of 88.5%.
In this step, different reaction conditions were tried. Such as: tributyltin chloride: lithium aluminum hydride ═ 1:3 or 1: 4. the reaction temperature (20 ℃, 40 ℃) and the reaction time (2h and 4h),
(2R,3S,4S,5S) -4,5, 6-tris-benzyloxy-3-benzyloxymethyl-2, 2-di-chloro-3-hydroxycyclohexanone: azobisisobutyronitrile (AIBN): tributyltin) ═ 1: 0.1: 3 or 1: 0.5:4), the reaction temperature (90 ℃, 110 ℃), the reaction time (1.5h, 2h), and the yield of the obtained product is 85.73-89.85%.
Step 10: synthesis of (1S) -1- (hydroxy) -2,3, 4-tris-benzyloxy-5- (2-hydroxy-1- (hydroxymethyl) ethylamino) -1-c-benzyloxymethyl-1, 2,3, 4-cyclohexanetetraol (Compound X)
440mg of (2R,3S,4S,5S) -2,3, 4-tris-benzyloxy-5-benzyloxymethyl-5-hydroxycyclohexanone obtained in step 9, 218.4mg of 2-amino-1, 3-propanediol and 5mL of methanol were charged into a reaction flask, and the mixture was dissolved by stirring and reacted at 30 ℃ for 18 hours. 202mg of sodium cyanoborohydride was added and the reaction was carried out for 26 hours. The mixture was concentrated under reduced pressure, 5mL of distilled water was added, and 1mol/L hydrochloric acid was slowly dropped until no bubbles were emitted. The mixture was extracted with 100mL of ethyl acetate, and the combined extracts were washed with 20mL of 1mol/L hydrochloric acid and 20mL of saturated sodium bicarbonate solution in that order, dried over anhydrous sodium sulfate, and concentrated to obtain 343.8mg of a yellow liquid product with a yield of 68.9%.
In this step, different reaction conditions were tried. Such as: the reaction temperature (20 ℃, 40 ℃) and the reaction time (16h, 24h, 21h, 29h) are adopted, and the yield of the obtained product is 65.75-67.25%.
Step 11: synthesis of voglibose
300mg of (1S) -1- (hydroxy) -2,3, 4-tris-benzyloxy-5- (2-hydroxy-1- (hydroxymethyl) ethylamino) -1-C-benzyloxymethyl-1, 2,3, 4-cyclohexanetetraol prepared in step 10, 15mL of methanol, and 1mL of formic acid were charged into a reaction flask, stirred to mix well, 80mg of catalyst 10% Pd-C was added, and H was introduced2And reacting for 18h at 35 ℃. Et3N was added to neutralize to neutrality, celite was filtered, the filter cake was washed with 20mL of methanol, the filtrate and the washings were combined, after concentration, 20mL of distilled water was added to dilute, 30mL of dichloromethane was used for extraction, and the aqueous phase was freeze-dried to give 127.3mg of voglibose as a white solid with a yield of 97.5%.
In this step, different reaction conditions were tried. If the reaction temperature is 30 ℃, 50 ℃ and the reaction time is 16h and 20h, the yield of the obtained product is 94.28-96.99%.
The invention provides a preparation method of voglibose, which comprises eleven reaction steps, synthesizing a compound V by taking glucose monohydrate and sodium acetate as raw materials, preparing a compound VIII by utilizing the compound V through addition reaction, ring-opening reaction and aldol condensation reaction, and obtaining the voglibose through amination reduction of the compound VIII. The method has the advantages of cheap and easily-obtained reaction raw materials, mild reaction conditions, simple operation of the post-treatment process, obvious saving of the production cost, improvement of economic benefits, low cost, suitability for industrial production and accordance with the currently pursued environmental protection and energy conservation concepts.
In step 2 of the present invention, compound I is reacted with p-toluenesulfonyl in glycosidation with lewis acid (BF3 · Et2O) as a catalyst, and then recrystallized from absolute ethanol-cyclohexane to obtain compound II in high yield of 95.8%. In the step 3-4, removing acetyl protecting group in the compound II by using sodium methoxide, and then obtaining a benzyl protected compound IV with the exposed hydroxyl at the anomeric position through benzyl protection and glucoside desulfurization. In the step 5, a cheap and easily-obtained dimethyl sulfoxide-acetic anhydride system is adopted to oxidize the hydroxyl of the compound IV into carbonyl to obtain an intermediate compound IV, the reaction yield of the step is improved to more than 98%, and the reaction condition is very mild and is insensitive to air and water vapor. The method adopts the paratoluensulfide to protect the anomeric position of the glucose, not only can avoid unpleasant taste, but also the product is solid and can be purified by a recrystallization method, thereby greatly improving the reaction yield. The total yield of the five-step reaction is up to 85.1%, and the method is simple, convenient and easy to operate, free of column chromatography purification, low in cost and environment-friendly.
In step 6 of the invention, the reaction yield is improved by limiting the reaction time, and the yield is close to 100%. In step 7 of the invention, compound VI is reduced to straight-chain alcohol by sodium borohydride to obtain ring-opening product compound VII which is an epimeric mixture. In step 8 of the invention, two free hydroxyls are oxidized into ketone by DMSO/TFAA, then organic base triethylamine is added to carry out intramolecular aldol condensation reaction to form a compound VIII, and the yield of the three-step reaction is up to 76.7%.
In step 10, the method provided by the invention uses sodium cyanoborohydride as a reducing agent, obtains the required unique alpha-configuration product with 73.1% yield and high stereoselectivity, avoids a complex separation process, and greatly improves the production efficiency. In the step 11 of the invention, the methanol-formic acid solvent system has better dissolving capacity to raw materials and products, can shorten the reaction time and improve the reaction yield, and uses 10 percent Pd-C as a catalyst to replace the original Pd-black, thereby further improving the reaction yield. In the post-treatment process, the invention can meet the purity requirement only by neutralizing formic acid, filtering and washing with DCM, thereby greatly improving the efficiency and reducing the reaction cost.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims (10)

1. A synthetic method of voglibose is characterized by comprising the following steps:
step 1: taking glucose monohydrate and sodium acetate as raw materials, and adding acetic anhydride to prepare a compound I, wherein the structural formula is as follows:
Figure FDA0003039211170000011
；
step 2: mixing the compound I prepared in the step (1) with p-methylthiophenol, stirring and dropwise adding Lewis acid (BF 3. Et2O) to perform glycosylation reaction to prepare a compound II, wherein the structural formula is shown in the specification;
Figure FDA0003039211170000012
；
and step 3: mixing the compound II prepared in the step 2 with sodium methoxide, reacting to obtain an intermediate, and then adding sodium hydride and benzyl bromide to obtain a compound III, wherein the structural formula is as follows:
Figure FDA0003039211170000013
；
and 4, step 4: adding N-bromosuccinimide (NBS) into the compound III prepared in the step 3 in batches, and carrying out oxidation reaction to obtain a compound IV, wherein the structural formula is as follows:
Figure FDA0003039211170000014
Figure FDA0003039211170000021
and 5: adding the compound IV prepared in the step 4 into dimethyl sulfoxide, dropwise adding acetic anhydride, and carrying out oxidation reaction to obtain a compound V, wherein the structural formula is as follows:
Figure FDA0003039211170000022
；
step 6: dropwise adding Lithium Diisopropylamide (LDA) solution into the compound V prepared in the step 5 to perform addition reaction to prepare a compound VI, wherein the structural formula is as follows:
Figure FDA0003039211170000023
；
and 7: adding sodium borohydride into the compound V prepared in the step 6 in batches, and carrying out a ring-opening reaction to prepare a compound VII, wherein the structural formula is as follows:
Figure FDA0003039211170000024
；
and 8: adding dimethyl sulfoxide and trifluoroacetic anhydride into an organic solvent, then adding the compound VII and triethylamine prepared in the step 7, and carrying out aldol condensation reaction to obtain a compound VIII, wherein the structural formula is as follows:
Figure FDA0003039211170000025
Figure FDA0003039211170000031
and step 9: mixing the compound VIII prepared in the step 8 with Azobisisobutyronitrile (AIBN) and tributyltin, heating under protective gas to perform reduction reaction to prepare a compound IX, wherein the structural formula is as follows:
Figure FDA0003039211170000032
；
step 10: the compound IX prepared in the step 9 reacts with 2-amino-1, 3-propanediol and methanol, and then sodium cyanoborohydride is added as a reducing agent to prepare a compound X, wherein the structural formula is as follows:
Figure FDA0003039211170000033
；
step 11: adding the compound X prepared in the step 10 and 10% Pd/C of a catalyst into a methanol-formic acid solvent system, introducing hydrogen, and carrying out reduction reaction to prepare voglibose, wherein the structural formula is as follows:
Figure FDA0003039211170000034
；
2. the method for synthesizing voglibose according to claim 1, wherein in the step 1, the reaction temperature is 100 ℃ and the reaction time is 1-5 h;
in the step 2, the reaction temperature is 20-40 ℃, and the reaction time is 4-8 h;
in the step 3, the reaction temperature is 10-20 ℃, and the reaction time is 0.5-1 h;
in the step 4, the reaction temperature is 20-40 ℃, and the reaction time is 0.5-2 h;
in the step 5, the reaction temperature is 15-25 ℃, and the reaction time is 10-25 h;
in the step 6, the reaction temperature is-50 to-80 ℃, and the reaction time is 1 to 2 hours;
in the step 7, the reaction temperature is 20-40 ℃, and the reaction time is 4-8 h;
in the step 8, the reaction temperature is-50 to-80 ℃, and the reaction time is 1 to 3 hours;
in the step 9, the reaction temperature is 90-110 ℃, and the reaction time is 1-2 h;
in the step 10, the reaction temperature is 20-40 ℃, and the reaction time is 40-50 h;
in the step 11, the reaction temperature is 30-50 ℃, and the reaction time is 16-20 h.
3. The method for synthesizing voglibose according to claim 1, wherein in the step 1, the molar ratio of the reactant glucose monohydrate to acetic anhydride is 1: (5-6);
in the step 2, the molar ratio of the compound I to the p-methylthiophenol is 1 (1-1.5);
in the step 3, the molar ratio of the compound II to sodium methoxide is 1 (4-5), the molar ratio of the compound II to sodium hydride is 1:5-7, and the molar ratio of the compound II to benzyl bromide is 1 (5-6);
in the step 4, the molar ratio of the compound III to the N-bromosuccinimide is 1: (3-4);
in the step 5, the molar ratio of the compound IV to the acetic anhydride is 1 (1-1.5);
in the step 7, the molar ratio of the compound VI to the sodium borohydride is 1: (1-2);
in the step 9, the molar ratio of the compound VIII to the Azobisisobutyronitrile (AIBN) and the tributyltin is 1 (0.1-0.5) to (3-4).
4. The method for synthesizing voglibose according to claim 1, wherein the LDA solution in step 6 is prepared from diisopropylamine and butyllithium.
5. The method for synthesizing voglibose according to claim 4, wherein the reaction conditions of diisopropylamine and butyllithium are as follows: the reaction temperature is-5 ℃ to-1 ℃, the reaction time is 1-2h, and the molar ratio of diisopropylamine to butyllithium is 1: (1-2).
6. The method for synthesizing voglibose according to claim 1, wherein in step 6, column chromatography is required after the ring-opening reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (6-10): 1.
7. the method for synthesizing voglibose according to claim 1, wherein in step 8, column chromatography is required after aldol condensation reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (6-12): 1.
8. the process for synthesizing voglibose according to claim 1, wherein in step 9, tributyltin is prepared by reacting tributyltin chloride with lithium aluminum hydride.
9. The method for synthesizing voglibose according to claim 8, wherein the reaction conditions of tributyltin chloride and lithium aluminum hydride are as follows: the reaction temperature is 20-40 ℃, the reaction time is 2-4h, and the molar ratio of tributyltin chloride to lithium aluminum hydride is 1 (3-4).
10. The method for synthesizing voglibose according to claim 1, wherein in step 9, column chromatography is required after the reduction reaction, a gradient eluent in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (3-8): 1.
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