CN107488156B - Synthesis method of amorphous glucitol - Google Patents
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Abstract
The invention discloses an amorphous (1S) -1, 5-dehydrated-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl]Phenyl radical]-D-glucitol synthesis method, which has the following reaction formula:
Description
Technical Field
The invention relates to a synthesis method of a medicinal compound, and particularly relates to a synthesis method of amorphous (1S) -1, 5-dehydration-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (dapagliflozin).
Background
Diabetes is one of the top ten fatal ranks of diseases in the united states. About 2500 million people suffer from diabetes, and this figure is increasing due to aging and the effects of obesity. Currently, about 3.82 million people worldwide suffer from diabetes, and data suggests that by 2035 years this figure will be expected to become 5.92 million people, accounting for about 10% of the total world population.
Sodium-glucose cotransporter type 2(SGLT2), a novel target for the treatment of diabetes, consists of 672 amino acids. SGLT2 is distributed in the kidney and is the major protein that controls the absorption of glucose in the raw urine and returns it to the blood. Therefore, inhibition of SGLT2 activity increases urinary glucose excretion and lowers blood glucose concentration.
Dapagliflozin (DGZ) with the chemical name of (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol and the CAS number of 461432-26-8, and the chemical structural formula is shown as formula 1. At present, the medicinal crystal form of dapagliflozin S-1, 2-propylene glycol monohydrate is jointly developed by Behcet-Mitsubishi-Bao corporation (BMS) and AstraZeneca, is approved by European drug administration (EMA) to be marketed in 11 months 2012, and is the first sodium-glucose cotransporter 2(SGLT2) inhibitor approved to be marketed for treating type 2 diabetes. By inhibiting SGLT2 channel in kidney, renal tubular blood sugar reabsorption is reduced, glucose is discharged through urine, and the purpose of reducing blood sugar and glycosylated hemoglobin (HbA1c) is achieved. SGLT2 inhibitors are insulin-independent and therefore can be applied at any stage of diabetes with the same hypoglycemic effect in both newly-diabetic patients and those taking insulin. The FDA in the united states approved its use for the treatment of type 2 diabetes mellitus in month 1 of 2014 under the trade name Farxiga.
The DGZ is stable, reversible and highly selective.the selectivity of DGZ for SGLT2 is much higher than that of DGZ for SGLT1, which is 1000-3000 times higher relative to the transporter for glucose reabsorption in the small intestine SGLT 1. based on SGLT2 acting mainly in the kidney, no transport or reabsorption of glucose or other carbohydrates is found in other organs, thus DGZ reduces side effects on other organs.
For the synthesis process of dapagliflozin 6, in the prior art, as shown in the following reaction formula 1, a compound 3 can be obtained from different starting materials through condensation reaction, the compound 3 is reduced to obtain a compound 4, the compound 4 is subjected to hydroxyl protection, the compound 4 is recrystallized by ethanol to obtain a compound 5-2, and the compound 5-2 is subjected to alkaline hydrolysis and free dispersion to obtain a target compound 6. Since impurities 5-2, 6-1, 6-2, 6-3 and 6-4 shown in chemical formula 2 are generated in the process, the impurities are difficult to completely remove, and the existing medicinal crystal form is dapagliflozin S-1, 2-propylene glycol monohydrate. Therefore, dapagliflozin 6 obtained in the prior art is usually used as an intermediate, and the quality thereof hardly reaches the pharmaceutical standard.
Reaction scheme 1
Chemical formula 2
In 2003, the synthesis method reported in patent US6515117B2 is to adopt the process to synthesize the target compound 6, and the method comprises the following steps: 1) synthesizing a compound 3; under the protection of argon, 2.5M n-butyllithium n-hexane solution is dropwise added into a mixed solution of 1 and 1 dry tetrahydrofuran/toluene (volume ratio of 1:2) at-78 ℃, stirring is continued for 30min after the dropwise addition is finished, then the mixed solution is added into 2 toluene solution cooled to-78 ℃ through a conduit, the feeding speed is controlled, the temperature of the reaction solution is kept below-70 ℃, stirring is carried out at-78 ℃ for 30min under the condition of heat preservation, and then a methanol solution of methanesulfonic acid (1-1.88 equivalent) is added to quench the reaction. The reaction solution was warmed to room temperature and stirred overnight. After the reaction, the reaction was quenched with an aqueous sodium bicarbonate solution, which was added to make the reaction solution weakly alkaline. Diluting with water, extracting with ethyl acetate for 3 times, mixing organic phases, washing with brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, dissolving the concentrated residual liquid with hot toluene, adding into n-hexane solution, separating out the solid, filtering, washing the filter cake with n-hexane for 2 times, and drying to obtain compound 3. 2) Synthesis of Compound 5-2 to-10 ℃ in a solution of dichloromethane/acetonitrile (volume ratio 1:1) in which 1 equivalent of 3 is dissolved, 2 equivalents of triethylsilane are added, then 1.5 equivalents of boron trifluoride ethyl ether are added dropwise, and the reaction temperature is maintained at-10 ℃ to-5 ℃. After the dripping is finished, the reaction is carried out for 5 hours at the temperature of below 0 ℃. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate. Directly carrying out rotary evaporation on the obtained solution, removing a volatile solvent, adding ethyl acetate and water into the residue, carrying out layering, extracting a water phase for 2 times by using ethyl acetate, combining organic phases, washing by using water, washing by using brine, drying, filtering and concentrating to obtain a yellow bubble-shaped substance 4, dissolving the yellow bubble-shaped substance 4 in a dichloromethane solution, carrying out acetylation under the action of pyridine/acetic anhydride and a catalyst DMAP (4-dimethylaminopyridine), and carrying out quenching reaction by using water after the reaction is finished. After layering, extracting the water phase for 2 times by using dichloromethane, combining the organic phases, washing for 2 times by using dilute hydrochloric acid aqueous solution, washing for 1 time by using brine, drying by using anhydrous magnesium sulfate, filtering, concentrating, and recrystallizing by using anhydrous ethanol to obtain the target compound 5-2. 3) Synthesis of Compound 6 to a solution of 5-2 in tetrahydrofuran/methanol/water (volume ratio 2:3:1) was added 1.16 equivalents of lithium hydroxide monohydrate and stirred at room temperature 20 ℃ overnight. After completion of the reaction, the solvent was removed by rotary evaporation, the residue was dissolved with ethyl acetate, washed once with brine, then once with an aqueous solution containing 5% potassium hydrogensulfate, washed again with brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and the oil obtained after removal of the solvent was dissolved with a minimum amount of dichloromethane and dried under vacuum to give a bubble containing compound 6 with a purity of 94%.
Another process route is also reported in patent US6515117B 2: after the compound 3 is obtained, firstly acetylating to protect hydroxyl, then using triethylsilane/boron trifluoride diethyl etherate to reduce, obtaining oily matter through post-treatment, dissolving the oily matter in ethyl acetate/hexane solution at 70 ℃, cooling and crystallizing to obtain a compound 5-2, and hydrolyzing the compound 5-2 with lithium hydroxide to obtain a compound 6.
The compound 6 obtained in the patent US6515117B2 is used as an intermediate, and impurities in the synthesis process are difficult to completely remove, so that the product quality can hardly reach the quality standard of medicines. In addition, the process route needs to be subjected to hydroxyl protection and deprotection reaction, the route is long, the yield is low (the total yield of the inventor is 7.57-16.8% after a plurality of experiments according to the process), and the method is not beneficial to industrial production.
In 2012, the synthesis method reported in patent CN102627676B is similar to the method reported in patent US6515117B2, the process route also needs to undergo protection and deprotection reaction of hydroxyl group, the route is longer, the yield is lower, and it is not beneficial to industrial production, and compound 6 is also used as an intermediate, and the product quality is difficult to reach the pharmaceutical standard.
In 2015, the synthesis method reported by patent CN104496952A is that halogenated benzene derivatives are prepared into a copper lithium reagent or a Grignard reagent by using n-butyllithium n-hexane solution at low temperature of-78 ℃, then the copper lithium reagent or the Grignard reagent is subjected to condensation reaction with 2,3,4, 6-tetraacetoxy- α -D-glucopyranose bromide to obtain a compound 5-1, the compound 5-1 is recrystallized to obtain a compound 5-2, and finally the compound 6 is subjected to alkali hydrolysis by lithium hydroxide
Reaction formula 3
In conclusion, the 6 obtained by the prior art is basically obtained by the method of alkaline hydrolysis of the acetylate 5-2, the total yield is low, the industrial production is not facilitated, and the quality of the finally obtained 6 hardly reaches the medicinal standard. Therefore, it is urgently needed to provide a synthesis process of amorphous form 6 which is easy for industrial production and can easily obtain medicinal standards, i.e. to provide a production process of amorphous form 6 which is low in cost, environment-friendly, high in yield and meets the medicinal standards.
Disclosure of Invention
The invention aims to provide a synthesis method of amorphous glucitol, in particular to a synthesis method of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (dapagliflozin).
A synthetic method of amorphous glucitol has the following reaction formula:
the method comprises the following steps:
1) carrying out condensation reaction on the compound 1 and the compound 2 to obtain a compound 3;
2) carrying out reduction reaction on the compound 3 to obtain a compound 4;
3) adding S-1, 2-propylene glycol and water into the compound 4 to react to obtain a crude product 5;
4) refining the crude product 5 for 2 times to obtain a compound 5;
5) dissociating the compound 5 by toluene and water to obtain a three-phase system (the upper layer is a toluene phase, the middle layer is a water phase, and the lower layer is a material layer), and layering to obtain a lower-layer material;
6) dissolving the lower layer material by a benign solvent, and then washing and dispersing to obtain an amorphous compound 6;
it is characterized in that the preparation method is characterized in that,
in the step 5), dissociating the compound 5 through methylbenzene and a water system, and layering to obtain a lower-layer material;
in the step 6), the lower layer material is dissolved by a benign solvent, washed by water and then subjected to reduced pressure concentration to obtain a foam-like substance;
dissolving the bubble-shaped object by using a benign solvent, and dropwise adding the bubble-shaped object into a poor solvent under the protection of inert gas; filtering under the protection of inert gas, and drying a filter cake to obtain an amorphous compound 6.
Preferably, the benign solvent is ethers, esters or chlorinated hydrocarbons, preferably, the benign solvent is methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, dichloromethane or chloroform;
preferably, the dosage of the benign solvent is 1-5 ml per gram of the compound 5, and preferably 2-4 ml per gram of the compound 5.
Preferably, the poor solvent is n-heptane, n-hexane, n-pentane; the dosage of the poor solvent is 8-15 ml per gram of the compound 5.
Preferably, during the reduction reaction of the compound 3, boron trifluoride diethyl etherate, triethylsilane and a solvent dichloromethane are added into a reaction kettle together, then a dichloromethane solution of the compound 3 is dropwise added, stirring is carried out under a heat preservation condition after the dropwise addition is finished, and after the reaction is finished, a saturated sodium carbonate aqueous solution is used for regulating the pH value of the solution to be neutral.
Preferably, in the reduction reaction, the reaction temperature is-20 ℃ to 20 ℃, preferably-15 ℃ to 10 ℃, and more preferably-10 ℃ to-5 ℃; the molar ratio of the reactants is: the compound 3 is boron trifluoride diethyl etherate and triethylsilane (1: 2-7) and (1: 3), preferably the compound 3 is boron trifluoride diethyl etherate and triethylsilane (1: 4-6.5) and (1.5-2.5).
Preferably, in the step 3), S-1, 2-propylene glycol and water are added into the compound 4, heating is carried out, after the mixture is dissolved and cleared, the mixture is slowly cooled and crystallized to obtain a crude product 5, and the crude product 5 is recrystallized by methyl tert-butyl ether for 2 times to obtain the compound 5.
After the compound 5 is dissociated and layered by toluene and a water system, an obtained lower material layer is dissolved by a benign solvent, then is washed by water for 2 times, an obtained organic phase is concentrated to remove the solvent, the toluene belt is steamed for 1 time to obtain a bubble-shaped object, the bubble-shaped object is dissolved by the benign solvent, and then is dripped into the poor solvent.
Dissociating the compound 5 by using toluene and water at the temperature of 5-60 ℃, preferably 10-45 ℃, more preferably 15-35 ℃, and dissociating and stirring for 0.5-1 h;
transferring into a separating funnel, and separating into three layers, wherein the upper layer is toluene, the middle layer is water, and the lower layer is feed liquid; under the protection of inert gas, dissolving feed liquid by using a benign solvent, dropwise adding the solution into a poor solvent, stirring for 0.5-1 h after the dropwise adding is finished, filtering under the protection of inert gas, draining, and vacuum drying at 30-50 ℃;
preferably, the dosage of the toluene and the water is respectively 10-20 ml per gram of compound 5 and 10-20 ml per gram of compound 5.
The method specifically comprises the following steps:
1) synthesizing a compound 3; in tetrahydrofuran/toluene mixed solution, under-70 ℃, starting material 1 firstly reacts with n-butyllithium, then carries out condensation reaction with starting material 2, after the condensation reaction is finished, a prepared methane sulfonic acid methanol solution is dripped, the reaction is carried out at 20-30 ℃ after the dripping is finished, after the reaction is finished, an oily crude product 3 is obtained through post-treatment, and the oily crude product is directly used for the next reaction without solidification treatment;
2) synthesizing a compound 4; reducing the crude product 3 by using triethylsilane/boron trifluoride diethyl etherate in a dichloromethane solution, quenching the reaction by using a saturated sodium carbonate aqueous solution after the reaction is finished, directly concentrating the obtained solution under reduced pressure, removing a low-boiling-point solvent, adding water and ethyl acetate for dissolving, adjusting the pH value of the reaction solution to 7 by using the saturated sodium carbonate aqueous solution, extracting a water phase by using ethyl acetate for 3 times after liquid separation, combining organic phases, washing by using saturated salt solution for 3 times, and concentrating the obtained organic phase under reduced pressure to obtain a yellow bubble solid 4;
3) preparing a second refined product 5; adding (S) - (+) -1, 2-propylene glycol and pure water into the yellow foamy solid 4, heating, dissolving, and cooling to obtain a crude product 5; refining the crude product 5 twice by methyl tert-butyl ether to obtain a second refined product 5; the purity of the secondary refined product 5 is more than 99.8 percent, the single impurity is less than 0.1 percent, the total impurity is less than 0.2 percent, and the ignition residue is less than 0.1 percent;
4) dissociating the second competitive products 5; adding toluene and water into the second refined product 5, stirring for 0.5-1 h at 5-60 ℃, transferring into a separating funnel, standing for layering (the upper layer is a toluene phase, the middle layer is a water phase, and the lower layer is a viscous liquid of 6), and discarding the middle water layer and the upper toluene layer after layering; dissolving the lower layer of viscous material with benign solvent (methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, dichloromethane, chloroform, etc.), washing with purified water for 3 times, concentrating the obtained organic phase under reduced pressure to remove solvent, adding appropriate amount of toluene, steaming for 1 time to obtain bubble-shaped material 6;
5) preparing amorphous 6; the bubble 6 is dissolved using a benign solvent (methyl t-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, methylene chloride, chloroform, etc.). Dropwise adding the mixture into a poor solvent (n-heptane, n-hexane, n-pentane and the like) at the temperature of-15 ℃ under the condition of inert gas protection and stirring, continuing to keep the temperature and stir for 20-30min after dropwise adding, then filtering under the inert gas protection, pumping, and then placing a filter cake into a vacuum drying oven at the temperature of 40-50 ℃ for reduced pressure drying for 24-48 h to obtain amorphous 6 with the purity of more than 99.8%, the single impurity content of less than 0.1%, the total impurity content of less than 0.2%, and the ignition residue content of less than 0.1%, wherein the amorphous 6 meets the quality standard of medicines.
The positive progress effects of the invention are as follows: compared with the prior art for preparing amorphous 6, the method shortens the reaction steps, does not need hydroxyl protection and deprotection reaction, directly obtains secondary refined product 5 (the HPLC content is more than 99.8 percent, the single impurity is less than 0.1 percent, and the total impurity is less than 0.2 percent) from the crude product 5 through 2 times of recrystallization, and obtains the high-purity amorphous 6 from the secondary refined product 5 through dissociation and dispersion. The preparation process has mild reaction conditions and simple and convenient operation, and is suitable for industrial production; the total yield of the product is high, 43-53%, and medicinal amorphous 6 (the HPLC content is more than 99.8%, the single impurity content is less than 0.1%, the total impurity content is less than 0.2%, and the ignition residue, the solvent residue, the water content and the like all meet medicinal standards) can be easily obtained.
Detailed Description
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. In the preparation examples described below, NMR was measured by a Varian Inova-400 NMR spectrometer with TMS as internal standard and chemical shift in ppm; HPLC was determined by Waters1525 high performance liquid chromatograph.
Wherein in the synthesis method, the specific steps are as follows,
EXAMPLE 1 preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol
1) Synthesis of Compound 3
Under the protection of nitrogen, toluene (500.0ml), tetrahydrofuran (400.0ml) and a compound 1(200.00g, 614.19mmol) are sequentially added into a reaction bottle, liquid nitrogen is cooled to below-70 ℃, 2.5M n-butyllithium n-hexane solution (270.25ml, 675.61mmol) is dropwise added, after dropwise addition, the mixture is stirred for 10min under heat preservation, a toluene solution (500.0ml) of a compound 2(344.10g, 737.03mmol) is dropwise added, after dropwise addition, the mixture is stirred for 30-60min under heat preservation, and the reaction is monitored by TLC. After the reaction was completed, a solution of prepared methanesulfonic acid (80.0ml, 1.23mol) in methanol (500.0ml) was added dropwise, and the mixture was reacted at 20 to 30 ℃. And monitoring the reaction by TLC, and adjusting the pH of the reaction solution to be more than or equal to 7 by using saturated sodium carbonate aqueous solution or sodium bicarbonate aqueous solution after the reaction is finished. After separation, the aqueous phase was extracted 3 times with ethyl acetate, and the extracts were combined with the organic phase and concentrated under reduced pressure. The concentrated residue was taken up in ethyl acetate and washed 2 times with saturated aqueous sodium chloride solution, and the resulting organic phase was concentrated directly under reduced pressure to give crude oil 3(283.00g, 536.92mmol) with an HPLC content of 83.27% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 87.42%. The mixture is directly used for the next reaction without curing treatment.
2) Synthesis of Compound 4
Under nitrogen protection, dichloromethane (730ml), triethylsilane (210.9ml, 1.32mol) and boron trifluoride diethyl etherate (412.7ml, 1.58mol) were added to a reaction flask in this order, cooled to-10 to-0 ℃, 3(282.50g, 535.97mmol) dichloromethane solution (340ml) was added dropwise, after completion of dropping, stirring was carried out under heat preservation for 1.5 hours, the reaction was quenched with saturated aqueous sodium carbonate solution (282.5ml), the resulting solution was directly concentrated under reduced pressure, the low-boiling solvent was removed, water (250.0ml) and ethyl acetate (500.0ml) were added and dissolved under stirring, the pH of the reaction solution was adjusted to 7 with saturated aqueous sodium carbonate solution, after separation, the aqueous phase was extracted 2 times with ethyl acetate, 150 ml/time of ethyl acetate was used, the extract was combined with the organic phase, washed 3 times with saturated aqueous salt solution, 100 ml/time, the resulting organic phase was concentrated under reduced pressure to obtain yellow foamy solid 4(220.00g, 435.83mmol), HPLC content 80.23% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 80.54%.
3) Preparation of refined product 5
Adding (S) - (+) -1, 2-propylene glycol (399.2ml) and pure water (1170.0ml) into yellow foamy solid 4(219.50g, 434.84mmol), heating and stirring, slowly cooling after dissolving, stirring and crystallizing, filtering and draining to obtain crude product 5(284.0 g); the crude product 5 was recrystallized directly from methyl tert-butyl ether (1600ml) without drying, filtered and then drained to give a fine product 5(240.0 g); and (3) recrystallizing again by using methyl tert-butyl ether (1600ml) without drying, filtering, washing a filter cake for 2 times by using a proper amount of methyl tert-butyl ether, draining, and drying in an air-blast drying oven at 45-50 ℃ to obtain a secondary refined product 5(160.00g, 318.04mmol) with the HPLC purity of 99.98% [ HPLC normalization method: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 73.14%.
4) Free of the second refined product 5
Adding the second refined product 5(70.50g, 140.14mmol) into a reaction bottle containing toluene (500.0ml) and water (500.0ml), stirring at 25 deg.C for 30min, transferring into a separating funnel, standing for layering (upper layer is toluene phase, middle layer is water phase, and lower layer is 6 viscous liquid), and discarding middle layer water layer and upper layer toluene layer; dissolving the lower layer of viscous material with methyl tert-butyl ether (500ml), washing with purified water for 3 times, concentrating the obtained organic phase under reduced pressure to remove solvent, adding appropriate amount of toluene, and steaming for 1 time to obtain foam 6.
5) Preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (6)
Dissolving the foam 6 by using methyl tert-butyl ether (200.0ml), dropwise adding the dissolved foam 6 into n-heptane at-15 ℃ under the conditions of inert gas protection and stirring, continuously keeping the temperature and stirring for 20-30min after dropwise adding, then filtering under the condition of inert gas protection, draining, and placing a filter cake into a vacuum drying oven at 40-50 ℃ for decompression and drying for 24-48 h to obtain amorphous 6(53.94g, 131.87mmol) with the HPLC content of 99.96% [ HPLC normalization method: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], ESI-MS (m/z): 431.0[ M + Na ] +, 1H NMR (400MHz, CDCl3) delta: 7.22(d, J ═ 8.2Hz, 1H), 7.16-7.04(m, 2H), 6.97(d, J ═ 8.6Hz, 2H), 6.69(d, J ═ 8.6Hz, 2H), 5.27(s, 1H), 5.03(s, 1H), 4.06(s, 1H), 3.90(t, J ═ 8.3Hz, 2H), 3.85-3.78(m, 2H), 3.65(s, 2H), 3.58-3.39(m, 2H), 3.39-3.10(m, 4H), 1.28(t, J ═ 7.0Hz, 3H). The yield thereof was found to be 94.08%.
EXAMPLE 2 preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (dapagliflozin)
1) Synthesis of Compound 3
Under the protection of nitrogen, sequentially adding toluene (430.0ml), tetrahydrofuran (400.0ml) and a compound 1(200.00g, 614.19mmol) into a reaction bottle, cooling to below-70 ℃ by liquid nitrogen, dropwise adding a 2.5M n-butyllithium n-hexane solution (294.81ml, 737.03mmol), stirring at the constant temperature for 10min after dropwise adding, dropwise adding a toluene solution (370.0ml) of a compound 2(344.10g, 737.03mmol), stirring at the constant temperature for 30-60min after dropwise adding, and monitoring the reaction by TLC. After the reaction was completed, a solution of prepared methanesulfonic acid (80.0ml, 1.23mol) in methanol (600.0ml) was added dropwise, and the mixture was reacted at 20 to 30 ℃. And monitoring the reaction by TLC, and adjusting the pH of the reaction solution to be more than or equal to 7 by using saturated sodium carbonate aqueous solution or sodium bicarbonate aqueous solution after the reaction is finished. After separation, the aqueous phase was extracted 3 times with ethyl acetate, and the extracts were combined with the organic phase and concentrated under reduced pressure. The concentrated residue was taken up in ethyl acetate and washed 2 times with saturated aqueous sodium chloride solution, and the resulting organic phase was concentrated directly under reduced pressure to give crude oil 3(307.22g, 568.73mmol) with an HPLC content of 81.25% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 92.60%. The mixture is directly used for the next reaction without curing treatment.
2) Synthesis of Compound 4
Under the protection of nitrogen, dichloromethane (750.0ml), triethylsilane (136.69ml, 855.80mmol) and boron trifluoride diethyl etherate (267.51ml, 997.07mmol) are added into a reaction bottle in sequence, the mixture is cooled to-10 to-0 ℃, 3(189.46g, 350.74mmol) dichloromethane solution (340ml) is added dropwise, after the dropwise addition, the mixture is stirred at the temperature for 1.5h, saturated sodium carbonate aqueous solution (200.0ml) is used for quenching reaction, the obtained solution is directly concentrated under reduced pressure, after low boiling point solvent is removed, water (200.0ml) and ethyl acetate (500.0ml) are added for stirring and dissolving, the pH value of the reaction solution is adjusted to 7 by using saturated sodium carbonate aqueous solution, after liquid separation, the aqueous phase is extracted by ethyl acetate for 2 times, ethyl acetate 100 ml/time is used, the extract liquid is combined with the organic phase, the organic phase is washed by saturated saline water for 3 times and 100 ml/time, the obtained organic phase is concentrated under reduced pressure, yellow bubble solid 4(131.80 g), 295.17mmol), HPLC content 91.57% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 84.16%.
3) Preparation of refined product 5
Adding (S) - (+) -1, 2-propylene glycol (296.0ml) and pure water (866.0ml) into the yellow foamy solid 4(131.77g, 295.11mmol), heating and stirring, slowly cooling after dissolving, stirring and crystallizing, filtering and draining to obtain a crude product 5; directly recrystallizing the crude product 5 by using methyl tert-butyl ether (900ml) without drying, filtering and then pumping to obtain a refined product 5; without drying, recrystallizing again with methyl tert-butyl ether (900ml), filtering, rinsing the filter cake with an appropriate amount of methyl tert-butyl ether for 2 times, draining, and drying in a forced air drying oven at 45-50 deg.C to obtain secondary refined product 5(116.37g, 231.22mmol) with HPLC purity of 99.94% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 78.35%.
4) Free of the second refined product 5
Adding the secondary refined product 5(70.50g, 140.14mmol) into a reaction bottle containing toluene (500.0ml) and water (500.0ml), stirring at 30 ℃ for 30min, then transferring into a separating funnel while hot, standing for layering (the upper layer is a toluene phase, the middle layer is a water phase, and the lower layer is a viscous liquid of 6), and after layering, discarding the middle layer water layer and the upper layer toluene layer; dissolving the lower layer of viscous material with methyl tert-butyl ether (500ml), washing with purified water for 3 times, concentrating the obtained organic phase under reduced pressure to remove solvent, adding appropriate amount of toluene, and steaming for 1 time to obtain foam 6.
5) Preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (6)
Dissolving the foam 6 by using methyl tert-butyl ether (150.0ml), dropwise adding the dissolved foam 6 into n-heptane at the temperature of-15 ℃ under the conditions of inert gas protection and stirring, continuously keeping the temperature and stirring for 20-30min after dropwise adding, then filtering under the condition of inert gas protection, draining, and placing a filter cake into a vacuum drying oven at the temperature of 40-50 ℃ for decompression and drying for 24-48 h to obtain amorphous 6(56.6g, 138.35mmol) with the HPLC content of 99.94% [ HPLC normalization method: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 98.70%.
EXAMPLE 3 preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol
1) Synthesis of Compound 3
Under the protection of nitrogen, toluene (500.0ml), tetrahydrofuran (400.0ml) and a compound 1(200.00g, 614.19mmol) are sequentially added into a reaction bottle, liquid nitrogen is cooled to below-70 ℃, 2.5M n-butyllithium n-hexane solution (270.25ml, 675.61mmol) is dropwise added, after dropwise addition, the mixture is stirred for 10min under heat preservation, a toluene solution (500.0ml) of a compound 2(344.10g, 737.03mmol) is dropwise added, after dropwise addition, the mixture is stirred for 30-60min under heat preservation, and the reaction is monitored by TLC. After the reaction was completed, a solution of prepared methanesulfonic acid (80.0ml, 1.23mol) in methanol (500.0ml) was added dropwise, and the mixture was reacted at 20 to 30 ℃. And monitoring the reaction by TLC, and adjusting the pH of the reaction solution to be more than or equal to 7 by using saturated sodium carbonate aqueous solution or sodium bicarbonate aqueous solution after the reaction is finished. After separation, the aqueous phase was extracted 3 times with ethyl acetate, and the extracts were combined with the organic phase and concentrated under reduced pressure. The concentrated residue was taken up in ethyl acetate and washed 2 times with saturated aqueous sodium chloride solution, and the resulting organic phase was concentrated directly under reduced pressure to give crude oil 3(298.73g, 597.05mmol) with an HPLC content of 87.72% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 97.21%. The mixture is directly used for the next reaction without curing treatment.
2) Synthesis of Compound 4
Under the protection of nitrogen, dichloromethane (750.0ml), triethylsilane (250.0ml, 1.57mmol) and boron trifluoride diethyl etherate (470.0ml, 1.75mol) are added into a reaction bottle in sequence, the mixture is cooled to-10 to-0 ℃, 3(298.50g, 596.59mmol) dichloromethane solution (340ml) is added dropwise, after the dropwise addition, the mixture is kept at the temperature and stirred for 1.5h, saturated sodium carbonate aqueous solution (200.0ml) is used for quenching reaction, the obtained solution is directly concentrated under reduced pressure, after removing low-boiling point solvent, water (200.0ml) and ethyl acetate (500.0ml) are added for stirring and dissolving, then the pH value of the reaction solution is adjusted to 7 by using saturated sodium carbonate aqueous solution, after liquid separation, the aqueous phase is extracted by ethyl acetate for 2 times, ethyl acetate is used for 100 ml/time, the extract liquid is combined with the organic phase, washed by saturated saline water for 3 times and 100 ml/time, the obtained organic phase is concentrated under reduced pressure, yellow bubble solid 4(240.38 g), 539.99mmol), HPLC content 91.85% [ HPLC normalization: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 90.51%.
3) Preparation of refined product 5
Adding (S) - (+) -1, 2-propylene glycol (546.0ml) and pure water (1400.0ml) into yellow foamy solid 4(240.10g, 537.81mmol), heating and stirring, slowly cooling after dissolving, stirring and crystallizing, filtering and draining to obtain crude product 5; directly recrystallizing the crude product 5 by using methyl tert-butyl ether (1050ml) without drying, filtering and then pumping to obtain a refined product 5; and (3) recrystallizing again by using methyl tert-butyl ether (1050ml) without drying, filtering, washing a filter cake for 2 times by using a proper amount of methyl tert-butyl ether, draining, and drying in an air-blast drying oven at 45-50 ℃ to obtain a secondary refined product 5(174.21g, 346.25mmol) with the HPLC purity of 99.97% [ HPLC normalization method: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 64.38%.
4) Free of the second refined product 5
Adding the secondary refined product 5(70.50g, 140.12mmol) into a reaction bottle containing toluene (500.0ml) and water (500.0ml), stirring at 35 deg.C for 30min, transferring into a separating funnel while hot, standing for layering (upper layer is toluene phase, middle layer is water phase, and lower layer is 6 viscous liquid), and discarding middle layer water layer and upper layer toluene layer; dissolving the lower layer of viscous material with methyl tert-butyl ether (500ml), washing with purified water for 3 times, concentrating the obtained organic phase under reduced pressure to remove solvent, adding appropriate amount of toluene, and steaming for 1 time to obtain foam 6.
5) Preparation of amorphous (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -D-glucitol (6)
Dissolving the foam 6 by using methyl tert-butyl ether (150.0ml), dropwise adding the dissolved foam 6 into n-heptane at-15 ℃ under the conditions of inert gas protection and stirring, continuously keeping the temperature and stirring for 20-30min after dropwise adding, then filtering under the condition of inert gas protection, draining, and placing a filter cake into a vacuum drying oven at 40-50 ℃ for decompression and drying for 24-48 h to obtain amorphous 6(55.92g, 136.71mmol) with the HPLC content of 99.96% [ HPLC normalization method: chromatography column Agilent SB-C18 (250X 4.6mm 5 μm); a mobile phase, acetonitrile-water-trifluoroacetic acid (30: 70: 0.025) is used as a mobile phase A, acetonitrile-water-trifluoroacetic acid (90: 10: 0.025) is used as a mobile phase B, and gradient elution (0 → 20 min: A100% → 70%, 20 → 40 min: A70% → 10%, 40 → 50 min: A10%, 50 → 50.1 min: A100%, 50.1 → 60 min: A100%,) is carried out, wherein the detection wavelength is 220 nm; the column temperature is 30 ℃; flow rate, 1.0ml/min ], yield 97.57%.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to limit the present invention, and those skilled in the art can make variations and modifications of the present invention without departing from the spirit and scope of the present invention by using the methods and technical contents disclosed above.
Claims (10)
1. A synthetic method of amorphous dapagliflozin has the following reaction formula:
the method comprises the following steps:
1) carrying out condensation reaction on the compound 1 and the compound 2 to obtain a compound 3;
2) carrying out reduction reaction on the compound 3 to obtain a compound 4;
3) adding S-1, 2-propylene glycol and water into the compound 4 to react to obtain a crude product 5;
4) refining the crude product 5 by secondary recrystallization of methyl tert-butyl ether to obtain a compound 5;
5) dissociating the compound 5 by toluene and water to obtain a three-phase system, wherein the upper layer is a toluene phase, the middle layer is a water phase, the lower layer is a material layer, and layering to obtain a lower material layer;
6) dissolving the lower layer material by a benign solvent, and then washing and dispersing to obtain an amorphous compound 6;
it is characterized in that the preparation method is characterized in that,
during the reduction reaction of the compound 3, boron trifluoride diethyl etherate, triethylsilane and a solvent dichloromethane are added into a reaction kettle together, then a dichloromethane solution of the compound 3 is dripped, the mixture is stirred while keeping the temperature after dripping, and after the reaction is finished, a saturated sodium carbonate aqueous solution is used for adjusting the pH value of the solution to be neutral;
in the step 6), the lower layer material is dissolved by a benign solvent, washed by water and then subjected to reduced pressure concentration to obtain a foam-like substance;
dissolving the bubble-shaped object by using a benign solvent, dropwise adding the bubble-shaped object into a poor solvent under the protection of inert gas, filtering under the protection of inert gas, and drying a filter cake to obtain an amorphous compound 6;
the benign solvent is methyl tert-butyl ether; the poor solvent is n-heptane.
2. The method of synthesis according to claim 1,
the dosage of the methyl tert-butyl ether is 1-5 ml per gram of the compound 5.
3. The synthesis method according to claim 1 or 2, wherein the amount of the methyl tert-butyl ether used is 2-4 ml per gram of the compound 5.
4. The synthesis method according to claim 1, wherein the n-heptane is used in an amount of 8-15 ml per gram of compound 5.
5. The synthesis method according to claim 1, wherein in the reduction reaction, the reaction temperature is-20 ℃ to 20 ℃, and the molar ratio of reactants is as follows: the compound 3 is boron trifluoride ethyl ether, triethylsilane (1-7) and (1-3).
6. The synthesis method of claim 5, wherein in the reduction reaction, the reaction temperature is-15 ℃ to 10 ℃; the molar ratio of the reactants is: and a compound 3 comprising boron trifluoride diethyl etherate and triethylsilane (1: 4 to 6.5) and (1.5 to 2.5).
7. The synthesis method according to any one of claims 1 to 2, wherein after the compound 5 is separated into layers by free toluene and water systems, the lower material layer is dissolved by methyl tert-butyl ether and then washed by water for 2 times, the obtained organic phase is concentrated to remove the solvent, toluene is steamed for 1 time to obtain bubbles, and then the bubbles are dissolved by methyl tert-butyl ether and then added dropwise into n-heptane.
8. The synthesis method of claim 7, wherein the amount of the toluene and methyl tert-butyl ether is 10-20 ml per gram of compound 5, and the amount of water used in each time is 0.3-1 times of that of the toluene or methyl tert-butyl ether used.
9. The method of synthesis according to claim 7,
dissociating the compound 5 by using toluene and water at the temperature of 5-60 ℃ for 0.5-1 h;
transferring into a separating funnel, and separating into three layers, wherein the upper layer is a toluene phase, the middle layer is a water phase, and the lower layer is a feed liquid layer; under the protection of inert gas, dissolving feed liquid by using methyl tert-butyl ether, dropwise adding the dissolved feed liquid into n-heptane, stirring for 0.5-1 h after dropwise adding, filtering under the protection of inert gas, draining, and vacuum drying at 30-50 ℃.
10. The synthesis method according to claim 8, wherein the temperature for dissociating the compound 5 by using toluene and water is 10 to 45 ℃; the dosage of the toluene and the water is respectively 10-20 ml per gram of compound 5 and 10-20 ml per gram of compound 5.
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