CN113549042B - Preparation method of dapagliflozin - Google Patents
Preparation method of dapagliflozin Download PDFInfo
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- CN113549042B CN113549042B CN202110838496.XA CN202110838496A CN113549042B CN 113549042 B CN113549042 B CN 113549042B CN 202110838496 A CN202110838496 A CN 202110838496A CN 113549042 B CN113549042 B CN 113549042B
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Abstract
The invention discloses a preparation method of dapagliflozin, which comprises the following steps: (1) reacting a compound solution shown as a formula II with an n-butyllithium solution in a first microreactor in a microchannel reaction device; (2) reacting the effluent of the first microreactor with the compound shown in the formula III in a second microreactor in a microchannel reaction device to obtain the compound shown in the formula IV; (3) carrying out reduction reaction on the compound shown in the formula IV in a third microreactor in a microchannel reaction device to obtain a compound shown in a formula V; (4) and (3) deprotecting the compound shown as the formula V to obtain dapagliflozin shown as the formula I. The method adopts the glucose lactone protected by benzyl as the starting material, avoids the generation and repeated derivatization of isomer impurities and ring-opening impurities, has higher stereoselectivity, and reduces the post-treatment steps and the generation of waste materials; meanwhile, the method has the advantages of high yield, high purity, few synthesis steps, simple and convenient operation and high safety.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of dapagliflozin.
Background
Dapagliflozin (Dapagliflozin) is a reversible, highly selective hypoglycemic drug with the trade name of Farxiga, and is mainly used for improving the blood sugar control of type 2 diabetic patients. The mechanism of action is to reduce plasma glucose levels by inhibiting SGLT2 expressed in the kidney to reduce glucose reabsorption by the renal tubules, allowing excess glucose to pass out of the body through the urine. Compared with the traditional hypoglycemic drug, the dapagliflozin can not cause adverse reactions such as hypoglycemia, weight gain and the like, can not cause serious gastrointestinal reaction, does not need injection administration, improves the compliance of the drug administration of patients, and has wide application prospect.
The chemical name of dapagliflozin is (2S,3R,4R,5S,6R) -2- [3- (4-ethoxybenzyl) -4-chlorphenyl ] -6-hydroxymethyl tetrahydro-2H-pyran-3, 4, 5-triol, the specific structure is shown as formula I,
the main synthetic route (route one) of dapagliflozin is: 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene exchanges with n-butyllithium-halogen at the low temperature of-78 ℃ to generate a phenyllithium derivative, then reacts with glucosolactone protected by Trimethylsilyl (TMS) to generate a glycosidic bond, the reaction solution is directly quenched with methanol and methanesulfonic acid solution, and then is reduced by triethylsilane and boron trifluoride diethyl etherate to remove methoxyl groups to obtain two types of crude dapagliflozin products, the crude products and acetic anhydride undergo acetylation reaction and then are recrystallized and purified, and finally, acetyl groups are removed to obtain the purified dapagliflozin products. The method has the defects that the steps are multiple, hydroxyl on a sugar ring is subjected to derivatization twice, more waste materials are generated, in the route, the gluconolactone can generate furan ring isomer impurities in the steps of anomeric carbon hydroxyl etherification and trimethyl silane protecting group removal, the impurities are not easy to remove, and the product yield is influenced. Secondly, in the halogen exchange reaction participated by the n-butyl lithium, chlorine of the 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene and the n-butyl lithium can possibly generate the halogen exchange reaction; the n-butyl lithium is active and inflammable, and has poor production safety and harsh low-temperature condition of-78 ℃.
Lemailre et al report a synthetic route shown in the second route, namely coupling aryl zinc derivatives with bromoglucose protected by pivaloyl, and finally removing the protecting group to obtain the purified product of the Griflozin. When the glucose compound in the synthetic route has a pivaloyl group, the compound needs to react with a bromine reagent, so that the process cost and steps are increased, and the problem of bromine reagent treatment is also involved.
Zhu et al reported that (2,3,4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) tributylstannane with stable configuration undergoes a stereo cross-coupling reaction with aromatic halide in the presence of a palladium catalyst (route III), and has strong stereocontrol. However, the use of metal catalysts such as palladium and copper in the reaction easily causes metal residues, affects the stability of the drug, and is not suitable for industrial production.
The Anna Sadurna group and Kuduva group also reported in 2018 that the benzyl-protected gluconolactone and aryl lithium derivative have cross-coupling reaction in turn, the stereoselectivity is high, but n-butyl lithium is used in the reaction, the safety is poor, the process is complicated, and the operation is inconvenient.
In conclusion, the main problems in the synthetic route are as follows: 1) the used trimethylsilyl and pivaloyl protecting group protected glucolactone needs multiple derivatization of hydroxyl on a sugar ring in the process, or needs a large amount of bromine reagent, easily generates isomer impurities and a large amount of waste materials, has long process steps and is not friendly to the environment. 2) In the process, n-butyllithium is mostly used for the cross-coupling reaction, the conditions are harsh, and the production safety is poor. Therefore, the invention provides a novel preparation method of dapagliflozin.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of providing a preparation method of dapagliflozin aiming at the defects of the prior art.
In order to solve the technical problem, the invention discloses a preparation method of dapagliflozin, which comprises the following steps:
(1) respectively and simultaneously pumping a compound solution shown as a formula II and an n-butyllithium solution into a first microreactor in a microchannel reaction device for reaction, wherein the obtained reaction liquid is a reaction liquid containing an aryl lithium compound;
(2) respectively pumping the effluent of the first microreactor and the compound shown in the formula III into a second microreactor in the microchannel reaction device simultaneously for reaction to obtain the compound shown in the formula IV;
(3) carrying out reduction reaction on the compound shown in the formula IV in a third microreactor in a microchannel reaction device to obtain a compound shown in a formula V;
(4) removing benzyl protection from the compound shown in the formula V to obtain dapagliflozin shown in the formula I;
wherein X is selected from bromine or iodine; preferably, X is bromine.
The microchannel reaction device comprises a micro mixer and a micro-structure reactor which are sequentially connected through a pipeline, wherein reaction raw materials are input into the micro mixer and subsequent equipment through a precise low-pulsation pump; wherein, the temperature of the reactor in the microchannel reaction device is controlled by a low-temperature constant-temperature stirrer.
In the step (1), the molar ratio of the compound shown as the formula II to n-butyllithium is 1: (1-1.5); preferably, the molar ratio of the compound represented by the formula II to n-butyllithium is 1: 1.1.
in the step (1), the solvent of the compound solution shown in the formula II is an organic solvent; preferably, the solvent is a mixture of toluene and/or tetrahydrofuran; further preferably, the solvent is toluene and tetrahydrofuran in a volume ratio of (0.5-3.5): 1; more preferably, the solvent is toluene and tetrahydrofuran in a volume ratio of (1-3): 1, in a mixture of the components.
In the step (1), the concentration of the compound solution shown as the formula II is 0.1-0.9 mmol/mL; preferably, the concentration of the compound solution shown in the formula II is 0.3-0.7 mmol/mL.
In the step (1), the solvent of the n-butyllithium solution is an organic solvent; preferably, the solvent of the n-butyllithium solution is n-hexane.
In the step (1), the concentration of the n-butyllithium solution is 0.5-4.5 mol/L; preferably, the concentration of the n-butyllithium solution is 1.5-3.5 mol/L; further preferably, the concentration of the n-butyllithium solution is 2-3 mol/L; still more preferably, the concentration of the n-butyllithium solution is 2.5 mol/L.
In the step (1), the pumping rate ratio of the compound solution shown in the formula II to the n-butyl lithium solution is (3.56-5.56): 1; preferably, the pumping rate ratio of the solution of the compound represented by the formula II to the n-butyllithium solution is 4.56: 1; further preferably, the pumping rate of the compound solution shown in the formula II is 1.28-3.28 mL/min, and the pumping rate of the n-butyllithium solution is 0.1-0.9 mL/min; still further preferably, the pumping rate of the compound solution shown in the formula II is 1.78-2.78 mL/min, and the pumping rate of the n-butyllithium solution is 0.3-0.7 mL/min; still more preferably, the pumping rate of the compound solution shown in the formula II is 2.18-2.38 mL/min, and the pumping rate of the n-butyllithium solution is 0.4-0.6 mL/min;
in the step (1), the reaction temperature is-50 to-38 ℃; preferably, the temperature of the reaction is-43 to-47 ℃; further preferably, the temperature of the reaction is-45 ℃.
In the step (1), the residence time of the reaction is 12-18 min; preferably, the residence time of the reaction is 14-16 min; further preferably, the residence time of the reaction is 15 min.
In the step (1), the volume of the first microchannel reactor is 33-50 mL; preferably, the volume of the first microchannel reactor is 37-46 mL; further preferably, the volume of the first microchannel reactor is 42 mL.
In the step (2), the molar ratio of the compound shown as the formula II to the compound shown as the formula III is 1: (1.1-1.8); preferably, the molar ratio of the compound represented by the formula II to the compound represented by the formula III is 1: 1.4.
in the step (2), the compound shown in the formula III exists in the form of a compound solution shown in the formula III.
Wherein the solvent of the compound solution shown in the formula III is an organic solvent; preferably, the solvent is toluene.
Wherein the concentration of the compound solution shown in the formula III is 0.47-1.47 mmol/mL; preferably, the concentration of the compound solution shown in the formula III is 0.77-1.37 mmol/mL.
In the step (2), the ratio of the pumping rate of the compound solution shown in the formula III to the pumping rate of the compound solution shown in the formula II is (0.2-1.2): 1; preferably, the ratio of the pumping rate of the compound solution shown in the formula III to the pumping rate of the compound solution shown in the formula II is (0.4-0.8): 1; further preferably, the pumping rate of the compound solution shown in the formula III is 0.6-2.6 mL/min; more preferably, the pumping rate of the compound solution shown in the formula III is 1-2.2 mL/min.
In the step (2), the reaction temperature is-50 to-38 ℃; preferably, the temperature of the reaction is-45 to-40 ℃; further preferably, the temperature of the reaction is-45 ℃.
In the step (2), the residence time of the reaction is 25-40 min; preferably, the residence time of the reaction is 30 min.
In the step (2), the volume of the second microchannel reactor is 110-175 mL; preferably, the volume of the second microchannel reactor is 122-142 mL; further preferably, the volume of the second microchannel reactor is 132 mL.
In the step (3), the reduction reaction is a reaction of a compound shown as a formula IV, triethylsilane and boron trifluoride diethyl etherate.
Wherein the molar ratio of the compound shown in the formula IV to the triethylsilane to the boron trifluoride diethyl etherate is 1: (1.8-2.2): (1.4-1.8); preferably, the molar ratio of the compound shown in the formula IV to the triethylsilane and the boron trifluoride diethyl etherate is 1: 2: 1.5.
in the step (3), the mixed solution of the compound shown in the formula IV and triethylsilane and boron trifluoride diethyl etherate are respectively and simultaneously pumped into a third microreactor in a microchannel reaction device for reduction reaction.
Wherein the solvent of the mixed solution of the compound shown in the formula IV and the triethylsilane is an organic solvent; further preferably, the solvent of the mixed solution of the compound shown in the formula IV and triethylsilane is dichloromethane and/or acetonitrile; still more preferably, the solvent of the mixed solution of the compound shown in the formula IV and triethylsilane is dichloromethane and acetonitrile; still more preferably, the solvent of the mixed solution of the compound represented by the formula IV and the triethylsilane is dichloromethane and acetonitrile according to a volume ratio of (0.1-1.9): 1, a mixed solvent; most preferably, the solvent of the mixed solution of the compound shown in the formula IV and the triethylsilane is dichloromethane and acetonitrile according to a volume ratio of 1: 1, a mixed solvent;
wherein in the mixed solution of the compound shown in the formula IV and triethylsilane, the concentration of the compound shown in the formula IV is 0.1-0.5 mmol/mL; preferably, the concentration of the compound shown in the formula IV is 0.2-0.4 mmol/mL.
Wherein in the mixed solution of the compound shown in the formula IV and triethylsilane, the concentration of triethylsilane is 0.2-1 mmol/mL; preferably, the concentration of the triethylsilane is 0.4-0.8 mmol/mL.
Wherein the pumping rate ratio of the mixed solution of the compound shown in the formula IV and triethylsilane to boron trifluoride diethyl etherate is (10-30): 1; preferably, the pumping rate ratio of the mixed solution of the compound shown in the formula IV and triethylsilane to boron trifluoride diethyl etherate is (15-25): 1; further preferably, the pumping rate ratio of the mixed solution of the compound shown in the formula IV and triethylsilane to boron trifluoride diethyl etherate is (18-22): 1; more preferably, the pumping rate of the mixed solution of the compound shown in the formula IV and the triethylsilane is 0.5-1.5 mL/min, and the pumping rate of the boron trifluoride diethyl etherate is 0.01-0.09 mL/min.
In the step (3), the temperature of the reaction is-30 to-5 ℃; preferably, the temperature of the reaction is-30 to-15 ℃; further preferably, the temperature of the reaction is-20 ℃.
The reaction in the step (3) is carried out for 20-30 min; preferably, the residence time of the reaction is 20 min.
In the step (3), the volume of the third microchannel reactor is 21-32 mL; preferably, the volume of the third microchannel reactor is 22 mL.
In step (4), the compound of formula V is deprotected by Pd/C and ammonium formate.
Wherein the molar ratio of the compound shown in the formula V, Pd/C and ammonium formate is 1: (0.25-0.3): (5-5.5); preferably, the molar ratio of the compound of formula V, Pd/C and ammonium formate is 1: 0.25: 5.3.
has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the method adopts the glucose lactone protected by benzyl as the starting material, avoids the generation and repeated derivatization of isomer impurities and ring-opening impurities, has higher stereoselectivity, and reduces the post-treatment steps and the generation of waste materials; meanwhile, the method has the advantages of high yield, high purity, few synthesis steps, simple and convenient operation and high safety.
(2) The reaction process of the invention adopts a microchannel reaction technology, improves the selectivity and production safety of the reaction, effectively inhibits the n-butyllithium and the chlorine of the 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene from generating halogen exchange reaction, and is more suitable for industrial production.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The compound represented by the formula II-1 described in the following examples is a compound represented by the formula II wherein X is bromine.
Example 1:
(1) synthesis of (3R,4S,5R,6R) -3,4, 5-tris (benzyloxy) -6- ((benzyloxy) methyl) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-2-ol (IV)
Dissolving 17.45g (53.6mmol) of the compound represented by the formula II-1 in 107mL of toluene-tetrahydrofuran (V (toluene): V (tetrahydrofuran) ═ 2: 1) to obtain a mixed solution A; taking 24mL of a 2.5mol/L n-butyl lithium n-hexane solution as a solution B; 39.37g (73.08mmol) of (3R,4S,5R,6R) -3,4, 5-tris (benzyloxy) -6- ((benzyloxy) methyl) tetrahydro-2H-pyran-2-one (III) was dissolved in 75mL of toluene to give a mixed solution C.
And respectively pumping the mixed solution A and the solution B into a first micro mixer under the protection of nitrogen, fully mixing, and reacting through a first micro-channel reactor to obtain reaction effluent containing the aryl lithium compound. Wherein the sample introduction rate of A is 2.28mL/min, the sample introduction rate of B is 0.5mL/min, the reaction volume of a first micro-channel of the micro-channel reaction device is 42mL, the reaction temperature is-45 ℃, and the reaction residence time is 15 min. And respectively pumping the effluent of the first microchannel reactor (reaction effluent containing aryl lithium compound) and the solution C into a second micromixer at the same time, fully mixing, and introducing into a second microchannel reactor for coupling reaction. Wherein the sample introduction rate of C is 1.60mL/min, the second microchannel reaction volume of the microchannel reaction device is 132mL, the reaction temperature is-45 ℃, and the reaction residence time is 30 min. After the reaction was completed, the system was slowly transferred to ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine to neutrality, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 39.98g of a pale yellow oily substance (iv) (used in the next reaction without purification) in a yield of 95%. ESI-MS, m/z: 807.3059[ M + Na ]] + ； 1 H NMR(400MHz,Chloroform-d)δ:7.15-7.39(m,21H),7.03(d,J＝8Hz,2H),6.92(d,J＝6.8Hz,2H),6.72(d,J＝8.8Hz,2H),4.85-4.88(m,3H),4.42-4.66(m,5H),4.10-4.12(m,1H),4,01-4.06(m,1H),3.90-3.97(m,3H),3.68-3.83(m,2H),3.67-3.70(m,2H),3.49(d,J＝9.2Hz,2H),1.35(t,J＝3.6Hz,3H)。
(2) Synthesis of (2R,3R,4R,5S) -3,4, 5-tris (benzyloxy) -2- ((benzyloxy) methyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran (V)
39.98g (50.9mmol) of the compound of the formula IV and 15.5mL (101.8mmol) of triethylsilane are dissolved in 170mL of dichloromethane-acetonitrile (V (dichloromethane): V (acetonitrile): 1) to give a mixed solution D, and 9.6mL (76.4mmol) of boron trifluoride diethyl ether are taken as a solution E.
Pumping the mixed solution D and the solution E into a third micro mixer respectively, mixing fully, and passing throughThe third microchannel reactor produces a reaction effluent comprising the compound of formula v. Wherein the sample introduction rate of D is 1.0mL/min, the sample introduction rate of E is 0.05mL/min, the third microchannel reaction volume of the microchannel reaction device is 21mL, the reaction temperature is-20 ℃, and the reaction residence time is 20 min. After the reaction, saturated sodium bicarbonate solution is added dropwise to quench the reaction, the organic phase is removed by decompression and concentration, water is added, and ethyl acetate is used for extraction. The combined organic phases were washed successively with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 35.64g of the compound of formula V in 91% yield. ESI-MS, m/z: 791.3162[ M + Na ]] + ； 1 H NMR(400MHz,Chloroform-d)δ:7.15-7.41(m,20H),7.03(d,J＝8.4Hz,2H),6.89(d,J＝5.6Hz,2H),6.71-6.88(m,3H),4.75-4.92(m,3H),4.45-4.65(m,3H),4.42-4.45(m,1H),4,38-4.40(m,1H),4.16(d,J＝9.6Hz,1H),4.06(d,J＝15.2Hz,1H),3.71-3.95(m,4H),3.66-3.68(m,1H),3.61-3.63(m,2H),2.48-3.51(m,2H),1.35(t,J＝2.8Hz,3H)。
(3) Synthesis of dapagliflozin (formula I)
15.47g (245.55mmol) of ammonium formate were dissolved in 180mL of methanol and stirred to dissolve it; 35.64g (46.32mmol) of the compound of the formula V and 12.30g Pd/C (10%) are added and the reaction is refluxed for 1 h. Rapidly cooling to room temperature, filtering, washing a filter cake with methanol, combining filtrate and washing liquor, and purifying by silica gel column chromatography to obtain 17.23g of white solid dapagliflozin, wherein the yield is 91%, the purity is 99.65%, and the content of single impurity of the product is less than 0.1% by LC/MS detection. ESI-MS, m/z: 431.1266[ M + Na ]] + ； 1 H NMR(400MHz,DMSO-d6)δ:7.36(d,J＝8.3Hz,1H),7.32(dd,J＝1.8Hz,1H),7.22(dd,J＝1.8Hz,8.3Hz,1H),7.09(d,J＝8.5Hz,2H),6.82(d,J＝8.4Hz,2H),4.83(s,1H),4.46(s,3H),3.89-4.05(m,5H),3.65-3.76(m,1H),3.40-3.45(m,1H),3.05-3.29(m,4H),1.29(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,DMSO-d6)δ:157.21,139.72,138.24,132.36,131.57,131.22,129.82,129.01,127.84,114.62,80.93,80.72,78.62,75.41,70.66,63.40,61.52,38.21,15.63。
Comparative example 1:
the same as example 1 except that the synthesis of the compound of formula iv and the compound of formula v was carried out in a reaction flask using conventional methods.
(1) Synthesis of Compounds of formula IV
15.0g (39.6mmol) of the compound represented by the formula II-1 was dissolved in 80mL of a mixed solution of toluene and tetrahydrofuran (V (toluene): V (tetrahydrofuran): 2: 1), the temperature was reduced to-78 ℃ under the protection of nitrogen, 20.6mL (50.67mmol) of an n-hexane solution of 2.5mol/L n-butyllithium was slowly injected into the reaction mixture by a syringe, the dropping speed was controlled so that the temperature of the reaction mixture was lower than-70 ℃, and the reaction was completed for 1.5 hours after the injection. Then, 34.74g (64.50mmol) of the compound of formula III in 65mL of toluene was slowly added to the reaction mixture, the dropping rate was controlled so that the temperature of the reaction mixture was lower than-70 ℃ and the reaction mixture was kept at this temperature for 5 hours. After the reaction was completed, the system was slowly transferred to ice water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine to neutrality, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 25.50g of a pale yellow oily substance (iv) (used in the next reaction without purification) in 82% yield and 98.21% purity. ESI-MS, m/z: 807.3059[ M + Na ]] + 。
(2) Synthesis of Compounds of formula V
25.0g (31.83mmol) of the compound of the formula IV is dissolved in 100mL of a mixed solvent of acetonitrile-dichloromethane (V (acetonitrile): V (dichloromethane): 1), cooled to-30 ℃, added with 9.68mL (63.7mmol) of triethylsilane, added with 6.03mL (47.8mmol) of boron trifluoride diethyl etherate, reacted at-30 ℃ for 3h, added with saturated sodium bicarbonate solution after the reaction is finished, quenched, concentrated under reduced pressure to remove the organic phase, added with water and extracted with ethyl acetate. The combined organic phases were washed successively with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give 18.58g of the compound of formula V in 76% yield and 97.86% purity. ESI-MS, m/z: 791.3162[ M + Na ]] + 。
(3) Synthesis of dapagliflozin (formula I)
12.0g (190.47mmol) of ammonium formate was dissolved in 140mL of methanol and stirred to dissolve it; 27.65g (35.93mmol) of the compound of the formula V and 9.54g Pd/C (10%) are added and the reaction is refluxed for 1 h. Rapidly cooling to room temperature, filtering, washing a filter cake with methanol, combining a filtrate and a washing liquid, and purifying by silica gel column chromatography to obtain 13.07g of dapagliflozin as a white solid, wherein the yield is 89% and the purity is 99.12%. ESI-MS, m/z: 431.1266[ M + Na ] +.
The final product dapagliflozin of the comparative example was less pure and the product was checked by LC/MS and found to contain 0.3% of the compound of formula iv as a residue and a similar structure, 0.4% of an impurity, which was not found in other articles. The reaction liquid in each reaction step is subjected to liquid phase detection, the impurities appear in the synthesis process of the compound shown in the formula IV, and the impurities can be obtained by forming an aryl lithium compound by n-butyl lithium and chlorine on the structure of 5-bromo-2-chloro-4' -ethoxy diphenylmethane (II-1) and then coupling the aryl lithium compound with the compound shown in the formula III. Meanwhile, during product detection, the impurities generated in the sugar lactone ring opening process in the compound shown in the formula IV are found, one is the impurity that the hydroxyl on the quaternary carbon is changed into carbonyl, the hydroxyl on the other quaternary carbon and the hydrogen on the adjacent carbon are eliminated to generate an impurity product with double bonds, the impurities exist, the purity of the final product is low, the obtained product is recrystallized, the purity of the recrystallized product is detected, and the content of single impurity in the dapagliflozin product can be reduced to 0.2%.
It can be seen that, in the example 1, the benzyl-protected gluconolactone is used as a raw material, and a microchannel technology is adopted, so that the conformation of the product can be effectively controlled, and by liquid phase detection, the conformation of the product in the example 1 is almost only one, the other conformational isomer is almost trace, and the selectivity is high; whereas comparative example 1 had a large amount of impurities and a single impurity content, which could be reduced to 0.2% only by recrystallization. The presence of these impurities can affect the efficacy and safety of the drug, and may have serious toxic effects.
The invention provides a method and a thought of a preparation method of dapagliflozin, and a plurality of methods and ways for realizing the technical scheme, the above description is only a preferred embodiment of the invention, and it should be noted that, for a person skilled in the art, a plurality of improvements and decorations can be made without departing from the principle of the invention, and the improvements and decorations should also be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (1)
1. The preparation method of dapagliflozin is characterized by comprising the following steps:
(1) dissolving 53.6mmol of a compound shown as a formula II in 107mL of toluene-tetrahydrofuran to obtain a mixed solution A, wherein,Vtoluene:Vtetrahydrofuran = 2: 1; 24mL of a 2.5mol/L n-hexane solution of n-butyllithium was used as a solution B; 73.08mmol of a compound shown as a formula III is dissolved in 75mL of toluene to obtain a mixed solution C;
respectively pumping the mixed solution A and the solution B into a first micro mixer under the protection of nitrogen, and reacting through a first micro-channel reactor to obtain reaction effluent liquid containing the aryl lithium compound after fully mixing; wherein the sample introduction rate of A is 2.28mL/min, the sample introduction rate of B is 0.5mL/min, the first microchannel reaction volume of the microchannel reaction device is 42mL, and the reaction temperature is-45% o C, the reaction retention time is 15 min;
pumping the effluent of the first microchannel reactor, which contains the reaction effluent of the aryl lithium compound, and the solution C into a second micro mixer simultaneously respectively, fully mixing, and introducing into a second microchannel reactor for coupling reaction; wherein the sample introduction rate of the solution C is 1.60mL/min, the second microchannel reaction volume of the microchannel reaction device is 132mL, and the reaction temperature is-45% o C, the reaction retention time is 30 min; after the reaction is finished, slowly transferring the system into ice water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution to be neutral, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a light yellow oily substance, namely the compound shown in the formula IV, which is directly used for the next reaction without purification;
(2) dissolving 50.9mmol of the compound shown in the formula IV and 101.8mmol of triethylsilane in 170mL of dichloromethane-acetonitrile to obtain a mixed solution D, wherein,Vdichloromethane:Vacetonitrile = 1: 1; taking 76.4mmol of boron trifluoride diethyl etherate as a solution E;
pumping the mixed solution D and the solution E into a third micro mixer respectively, and reacting through a third micro-channel reactor to obtain a reaction effluent containing the compound of the formula V after fully mixing; wherein the sample introduction rate of the mixed solution D is 1.0mL/min, the sample introduction rate of the solution E is 0.05mL/min, the third microchannel reaction volume of the microchannel reaction device is 21mL, the reaction temperature is-20 ℃, and the reaction residence time is 20 min; after the reaction is finished, dropwise adding saturated sodium bicarbonate solution to quench the reaction, decompressing and concentrating to remove an organic phase, adding water, and extracting by ethyl acetate; combining the organic phases, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a compound of formula V;
(3) 245.55mmol ammonium formate was dissolved in 180mL methanol and stirred to dissolve it; adding 46.32mmol of the compound of the formula V and 12.30g of 10% Pd/C, refluxing for 1h, rapidly cooling to room temperature, filtering, washing a filter cake with methanol, combining a filtrate and a washing liquid, and purifying by silica gel column chromatography to obtain a white solid dapagliflozin shown in the formula I;
wherein X is selected from bromine.
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| CN114805019B (en) * | 2022-04-25 | 2024-03-12 | 华东师范大学 | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology |
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Denomination of invention: Preparation method of Dapagliflozin Effective date of registration: 20230711 Granted publication date: 20220927 Pledgee: Xingye Bank Limited by Share Ltd. Anqing branch Pledgor: ANQING CHICO PHARMACEUTICAL CO.,LTD. Registration number: Y2023980047965 |
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Application publication date: 20211026 Assignee: Anhui Qixin Pharmaceutical Chemical Co.,Ltd. Assignor: ANQING CHICO PHARMACEUTICAL CO.,LTD. Contract record no.: X2023980037773 Denomination of invention: Preparation method of Dapagliflozin Granted publication date: 20220927 License type: Common License Record date: 20230712 |