CN117756610A - Synthesis method of dapagliflozin intermediate - Google Patents

Synthesis method of dapagliflozin intermediate Download PDF

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CN117756610A
CN117756610A CN202211128246.8A CN202211128246A CN117756610A CN 117756610 A CN117756610 A CN 117756610A CN 202211128246 A CN202211128246 A CN 202211128246A CN 117756610 A CN117756610 A CN 117756610A
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刘忠
时江华
孙权威
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing dapagliflozin intermediates. The invention provides a method for preparing dapagliflozin key intermediate 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene by taking (2-chloro-5-iodophenyl) methylamine as a raw material and reacting with 4-ethoxyphenylboronic acid under palladium catalysis after potassium iodide activation.

Description

Synthesis method of dapagliflozin intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing dapagliflozin intermediates.
Background
Dapagliflozin (Dapagliflozin), a commodity name of Farxiga, is the first approved sodium-dependent glucose transporter 2 (SGLT 2) inhibitor approved by the european union committee at 11, 12, 2012 and the us FDA at 1, 8, 2014. Chemical name: (2S, 3R,4R,5S, 6R) -2- [3- (4-ethoxyphenyl) -4-chlorophenyl ] -6-hydroxymethyltetrahydro-2H-pyran-3, 4, 5-triol:
the synthesis route reported by the original Bai-Shi Guibao company is the main stream synthesis technology of dapagliflozin at present, namely, compound 4, namely, 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene, is subjected to lithium-halogen exchange with n-butyllithium at a low temperature of minus 78 ℃ to generate phenyl lithium derivatives, then reacts with glucose lactone protected by Trimethylsilyl (TMS), namely, compound 3 to generate glycosidic bonds, the reaction solution is directly quenched by methanol and methanesulfonic acid solution, and is reduced by triethylsilane and boron trifluoride diethyl ether to remove methoxy groups to obtain dapagliflozin crude products with two configurations, the crude products react with acetic anhydride under the catalysis of 4-Dimethylaminopyridine (DMAP) and then are recrystallized and purified to obtain single beta-tetraacetdapagliflozin isomers, and finally, acetyl is removed by lithium hydroxide aqueous solution in a THF-methanol-water mixed solvent to obtain pure dapagliflozin products:
it is easy to see that the compound 4 is a key intermediate for synthesizing the compound, the synthesizing method thereof, liu Wenjie and the like are chemically researched and applied, 2016,28 (4): 530-533. It is reported that 5-bromo-2-chlorobenzoic acid is used as a raw material, acyl chlorination is carried out with oxalyl chloride under the catalysis of DMF, then the acyl chlorination is carried out with phenetole to obtain crude product 4-bromo-2-chloro-4' -methoxybenzophenone through Friedel-crafts acylation reaction, and after recrystallization by absolute ethyl alcohol, naBH is carried out 4 /AlCl 3 Or Et 3 SiH/BF 3 .Et 2 O is reduced to obtain an intermediate 5-bromo-2-chloro-4' -methoxyl diphenyl methane. In the reaction process of the Friedel-crafts acylation step, the use of a chloro reagent and Lewis acid represented by aluminum trichloride is greatly excessive, the post-treatment process is complicated, a large amount of acid gas and wastewater are easy to generate, the problems of environmental pollution and operation safety exist, the use is unfavorable for mass production, and the synthetic route is as follows:
wu Xue the synthesis of dapagliflozin intermediate (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone by one-pot method using 5-bromo-2-chloro-benzoic acid and phenetole as starting materials was reported in one-pot method, chemical journal [ J ]. 35, volume 7, and the synthetic route was as follows:
the route has a certain danger due to the use of a strong oxidant and red phosphorus, and is not suitable for industrial mass production.
In summary, the preparation reaction steps of the key intermediate compound 1-chloro-2- (4-ethoxybenzyl) -4-halogenated benzene are complicated, and the post-treatment is difficult, so that the production is not facilitated; directly purchasing the intermediate is expensive and is also disadvantageous in terms of production.
Disclosure of Invention
Aiming at a plurality of problems existing in the prior preparation of dapagliflozin key intermediate 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene, the invention provides a novel preparation method of 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
the preparation method of the dapagliflozin key intermediate 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene is characterized by comprising the following steps:
adding a compound SM-1, alkali A, methyl iodide and an organic solvent A into a reaction device, stirring and dissolving, stirring at room temperature until the reaction is finished, concentrating under reduced pressure, evaporating the solvent, washing the residual product by diethyl ether, drying to obtain a white solid, adding the obtained white solid and a compound SM-2, a catalyst and alkali B into a reaction bottle, adding an organic solvent B, stirring at a controlled temperature until the reaction is finished, and performing post-treatment on the reaction to obtain a compound I;
the synthetic route is as follows:
preferably, the base A is selected from one of potassium carbonate, sodium bicarbonate, sodium hydride and sodium hydroxide, wherein potassium carbonate is particularly preferred.
Preferably, the catalyst is selected from NHC-Pd (II) -Mp, pd (dppf) Cl 2 Bis (tricyclohexylphosphine) dichloridePalladium, NHC-Pd (II) -Mp is particularly preferred.
Preferably, the base B is selected from one of potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide sodium hydride, preferably potassium tert-butoxide.
Preferably, the feeding mole ratio of the compound SM-1, the compound SM-2, the alkali A, the methyl iodide, the catalyst and the alkali B in the step 1 is 1:1.0-1.8: 1.8 to 2.5:3.0 to 4.0:0.02 to 0.1:1.0 to 2.0, preferably 1:1.2:2.0:3.2:0.05:1.5.
Preferably, the organic solvent A is selected from one or a combination of ethanol, methanol, acetonitrile and tetrahydrofuran, and dichloromethane is preferred.
Preferably, the organic solvent B is selected from one or a combination of isopropanol, ethanol, methanol and tetrahydrofuran, wherein tetrahydrofuran is preferred.
Preferably, the reaction temperature is 60℃to 80℃and preferably 70℃to 75 ℃.
Preferably, after the reaction is finished, a post-treatment is needed, wherein the post-treatment is as follows: after the reaction, the reaction solution is filtered to remove the drying agent, the solvent is evaporated by decompression concentration, and the residual product is recrystallized by ethyl acetate and petroleum ether to obtain white solid I.
The invention has the beneficial effects that:
1. the invention provides a simple and efficient method for synthesizing dapagliflozin key intermediate 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene, which is characterized in that potassium iodide is used for activating benzylamine, so that the coupling reaction of boric acid is efficiently realized under palladium catalysis, the use of sulfonyl chloride is avoided, and meanwhile, the problem of low yield of Friedel-crafts reaction is solved.
2. The target product prepared by the process has higher yield and purity.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of the compound I, and the chromatographic conditions are as follows:
chromatographic column: YMC-Triart C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 270nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl.
Retention time: 27.3min
ESI-HRMS(m/z):373.6303[M+H] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ:7.65(s,1H),7.61(d,1H),7.18(d,1H),7.09(m,2H),6.85(m,2H),4.05(q,2H),3.99(s,2H),1.34(t,3H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:156.9,145.0,140.5,136.5,132.4,133.1,130.9,128.9,128.8,115.0,114.9,92.9,64.6,35.3,14.8。
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Synthesis of Compound I-1:
example 1
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved under stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized by ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in 98.8% purity of 99.92%.
Example 2
To a single-necked flask, SM-1 (60.79 g,0.20 mol), sodium carbonate (42.40 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and methanol (600 mL) were added and dissolved under stirring, and after completion of the reaction, the reaction was carried out at room temperature, potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (33.20 g,0.20 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and isopropyl alcohol (300 mL) were added to a double-necked flask under nitrogen protection, and vigorously stirred at 70℃for 15 hours, after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I with a yield of 94.6% purity of 99.77%.
Example 3
To a single-necked flask, compound SM-1 (60.79 g,0.20 mol), sodium bicarbonate (33.60 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and acetonitrile (600 mL) were added and dissolved with stirring, and after completion of the reaction, potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to obtain a white solid, and the obtained white solid was recrystallized from compound SM-2 (59.75 g,0.36 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and isopropyl alcohol (300 mL) under nitrogen protection in a double-necked flask with vigorous stirring at 70℃for 15 hours, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to obtain white compound I in a yield of 95.0%, 99.52% HPLC purity.
Example 4
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.36 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved with stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), sodium t-butoxide (28.83 g,0.3 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in a yield of 94.3% and a purity of 99.70%.
Example 5
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (69.11 g,0.5 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved with stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), lithium t-butoxide (24.01 g,0.3 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in a yield of 95.4% and a purity of 99.50%.
Example 6
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (85.16 g,0.6 mol) and tetrahydrofuran (600 mL) were added and dissolved with stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and isopropyl alcohol (300 mL) were added to a double-necked flask under nitrogen protection, and vigorously stirred at 70℃for 15 hours, after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1: 1) to give a white compound I with a yield of 94.8% and a purity of 99.73%.
Example 7
To a single-necked flask, SM-1 (60.79 g,0.20 mol), sodium hydride (9.60 g,0.40 mol), methyl iodide (113.55 g,0.8 mol) and ethanol (600 mL) were added and dissolved with stirring, and after completion of the reaction, the reaction was carried out at room temperature, potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (6.52 g,10.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and vigorously stirred at 70℃for 15 hours, after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I with a yield of 95.1% purity of 99.45%.
Example 8
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved under stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (2.61 g,4.0 mmol), potassium t-butoxide (33.66 g,0.3 mol) and ethanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in a yield of 94.8%, 99.77% HPLC purity.
Example 9
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved under stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (39.84 g,0.24 mol), NHC-Pd (II) -Mp (13.04 g,20 mmol), potassium t-butoxide (33.66 g,0.3 mol) and methanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized by ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in a yield of 95.5% and a purity of 99.42%.
Example 10
Adding compound SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) into a single-port bottle, stirring for dissolution, reacting at room temperature, filtering to remove potassium carbonate after the reaction is finished, concentrating under reduced pressure for evaporating solvent, washing the remaining product by diethyl ether, drying at 80 ℃ to obtain white solid, and adding compound SM-2 (39.84 g,0.24 mol), pd (dppf) Cl under the protection of nitrogen 2 (7.26 g,10.0 mmol), potassium tert-butoxide (22.44 g,0.2 mol) and tetrahydrofuran (300 mL) were added to a two-necked flask, the reaction was vigorously stirred at 70℃for 15 hours, after the completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in 94.5% yield and 99.62% HPLC purity.
Example 11
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (55.28 g,0.40 mol), methyl iodide (90.84 g,0.64 mol) and ethanol (600 mL) were added and dissolved with stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid was recrystallized from compound SM-2 (39.84 g,0.24 mol), bis-tricyclohexylphosphine palladium dichloride (7.38 g,10.0 mmol), potassium t-butoxide (44.88 g,0.4 mol) and isopropyl alcohol (300 mL) under nitrogen protection in a double-necked flask with vigorous stirring at 70℃for 15 hours, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in 94.8% purity, 99.51%.
Example 12
To a single-necked flask, SM-1 (60.79 g,0.20 mol), potassium carbonate (44.23 g,0.32 mol), methyl iodide (78.07 g,0.55 mol) and ethanol (600 mL) were added and dissolved with stirring, and after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (33.20 g,0.20 mol), NHC-Pd (II) -Mp (1.30 g,2.0 mmol), potassium t-butoxide (22.44 g,0.2 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in 84.3% purity 98.66%.
Example 13
To a single-necked flask, compound SM-1 (60.79 g,0.20 mol), potassium carbonate (76.02 g,0.55 mol), methyl iodide (120.065 g,0.85 mol) and ethanol (600 mL) were added and dissolved under stirring, after completion of the reaction, the potassium carbonate was removed by filtration, the solvent was distilled off by concentration under reduced pressure, the remaining product was washed with diethyl ether and dried at 80℃to give a white solid, and the obtained white solid, and compound SM-2 (66.40 g,0.40 mol), NHC-Pd (II) -Mp (14.34 g,22 mmol), potassium t-butoxide (49.37 g,0.44 mol) and isopropanol (300 mL) were added to a double-necked flask under nitrogen protection, and after completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from ethyl acetate/petroleum ether (200 mL, volume ratio 1:1) to give white compound I in a yield of 86.5%, HPLC purity 97.54%.

Claims (8)

1. The synthesis method of the dapagliflozin intermediate is characterized by comprising the following steps of:
adding a compound SM-1, alkali A, methyl iodide and an organic solvent A into a reaction device, stirring and dissolving, stirring at room temperature until the reaction is finished, concentrating under reduced pressure, evaporating the solvent, washing the residual product by diethyl ether, drying to obtain a white solid, adding the obtained white solid and a compound SM-2, a catalyst and alkali B into a reaction bottle, adding an organic solvent B, stirring at a controlled temperature until the reaction is finished, and performing post-treatment on the reaction to obtain a compound I;
the synthetic route is as follows:
2. the preparation method according to claim 1, wherein the alkali A is one selected from potassium carbonate, sodium bicarbonate, sodium hydride and sodium hydroxide.
3. The process according to claim 1, wherein the catalyst is selected from NHC-Pd (II) -Mp, pd (dppf) Cl 2 Bis (tricyclohexylphosphine) palladium dichloride.
4. The preparation method according to claim 1, wherein the base B is one selected from potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide sodium hydride.
5. The preparation method according to claim 1, wherein the compound SM-1, compound SM-2, base A, methyl iodide, catalyst and base B in the step 1 are fed in a molar ratio of 1:1.0-1.8: 1.8 to 2.5:3.0 to 4.0:0.02 to 0.1:1.0 to 2.0.
6. The preparation method according to claim 1, wherein the organic solvent A is one or a combination of ethanol, methanol, acetonitrile and tetrahydrofuran.
7. The preparation method according to claim 1, wherein the organic solvent B is one or a combination of isopropanol, ethanol, methanol and tetrahydrofuran.
8. The process according to claim 1, wherein the reaction temperature is 60℃to 80 ℃.
CN202211128246.8A 2022-09-16 2022-09-16 Synthesis method of dapagliflozin intermediate Pending CN117756610A (en)

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