CN116239582A - Engliflozin intermediate compound and preparation method thereof - Google Patents

Engliflozin intermediate compound and preparation method thereof Download PDF

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CN116239582A
CN116239582A CN202111517087.6A CN202111517087A CN116239582A CN 116239582 A CN116239582 A CN 116239582A CN 202111517087 A CN202111517087 A CN 202111517087A CN 116239582 A CN116239582 A CN 116239582A
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时江华
张洒洒
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Shandong New Time Pharmaceutical Co Ltd
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    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to an englitazone intermediate compound and a preparation method thereof. The invention takes (3S) -3- (4- ((2-chloro-5-iodophenyl) (methoxy) methyl) phenoxy) tetrahydrofuran as a starting material to react with hydroxy-protected bromopyranose under the catalysis of zinc and nickel to obtain a new intermediate compound of the engagliflozin. The invention also provides a method for preparing the englitjing by deprotection and reduction of the novel intermediate compound. The new intermediate provided by the invention has the advantages of simple synthesis method, short synthesis route for preparing the englitjing by using the new intermediate, high yield, mild reaction conditions and stable process, and is suitable for mass industrialized production.

Description

Engliflozin intermediate compound and preparation method thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an englitazone intermediate compound and a preparation method thereof.
Background
Engliflozin (empagliflozin), chemical name (2S, 3R,4R,5S, 6R) -2- [3- [4- [ (S) -tetrahydrofurane-3-yloxy ] benzyl ] -4-chlorophenyl ] -6-hydroxymethyl-epoxyhexane-3, 4, 5-triol, co-developed by Boringer' S Johner company and Gift, first approved by European drug administration (EMA) for 5 months in 2014, is an SGLT2 hypoglycemic drug which effectively reduces blood glucose, improves insulin sensitivity and islet beta cell function by a mechanism independent of insulin secretion and insulin action, and can reduce cardiovascular disease risk, heart disease and stroke for the first time, and has molecular weight: 450.91, CAS registry number 864070-44-0, having the following structural formula:
Figure BDA0003396836720000011
at present, the synthetic route of the carbon-aryl glycoside SGLT-2 inhibitor mainly comprises the steps of firstly preparing an aryl nucleophilic reagent, and then carrying out nucleophilic addition on D-glucolactone under the action of n-butyllithium: or coupling reaction with D-bromopyran glucose protected by hydroxyl to obtain saccharide key intermediate with aryl side chain, further deprotecting and reducing the intermediate to obtain englitazone, for example, in Chinese patent application CN105399735, compound 18, i.e. 5-iodo-2-chlorobenzoic acid is used as raw material, compound 21 is obtained through multi-step reaction, compound 21 is reduced by sodium borohydride-aluminum trichloride system to obtain compound 22, compound 22 reacts with n-butyllithium and zinc bromide-lithium bromide to generate coupling reaction with compound 5, beta conformational product 23 is selectively generated, and pivaloyl is removed from compound 23 under sodium methoxide condition to obtain target compound I. The method has the advantages of short synthetic route, mild reaction conditions, good stereoselectivity when pivaloyl is used for protection, high yield, but high price of (S) -3-hydroxytetrahydrofuran, and increased cost:
Figure BDA0003396836720000021
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under the acidic condition, the compound 21 undergoes a reduction reaction in a 1, 3-tetramethyl disilyl ether and aluminum trichloride system to obtain a compound 22, the compound 22 undergoes a Grignard reagent exchange reaction with isopropyl magnesium chloride/lithium chloride and then undergoes a nucleophilic addition reaction with an intermediate 3 to obtain a compound 24 under the action of citric acid, the compound 24 undergoes a reaction under the condition of hydrochloric acid-methanol solution to obtain a compound 25, and the compound 25 undergoes a demethoxy reaction under the action of triethylsilane-aluminum trichloride to obtain the target compound:
Figure BDA0003396836720000022
the method has the advantages of short synthetic route, high yield and mild reaction conditions. However, the (S) -3-hydroxytetrahydrofuran is relatively expensive, the synthesis cost is increased, and the post-treatment of the route is relatively complicated.
Patent WO2015101916 takes compound 26, namely 5-iodine (or bromine) -2-chlorobenzaldehyde, as a raw material, and compound 28 is obtained through multi-step reaction; or the compound 26 reacts with oxalyl chloride under the catalysis of DMF to obtain a compound 32, and the compound 32 reacts with fluoride under the action of Lewis acid aluminum trichlorideBenzene reaction to obtain compound 33, and under the action of strong alkali potassium tert-butoxide, compound 33 and (S) -3-hydroxytetrahydrofuran produce SN 2 Nucleophilic substitution reaction and reduction by sodium borohydride to give compound 28. Triethylamine is used as an acid binding agent, and trimethyl chlorosilane is used for protecting the hydroxyl of the compound 28 to obtain a compound 29; or compound 28 reacts with methanesulfonic acid to obtain compound 34, lithium-halogen exchange is carried out on compound 29 (or compound 34) and n-butyllithium at-70 ℃, nucleophilic addition is carried out on compound 29 and compound 3 to obtain compound 30, the hydroxyl of compound 30 (or compound 35) is converted into methyl ether by methanol solution of methanesulfonic acid to obtain compound 31, and two methoxy groups of compound 31 are removed in a triethylsilane and boron trifluoride diethyl ether solution system to obtain the target compound:
Figure BDA0003396836720000031
the method has longer synthetic route, the glycosyl and aryl side chain reaction still does not avoid the use of n-butyllithium, the post-treatment is complicated, and the reaction condition is very harsh, thereby being not beneficial to industrial production.
In view of the problems in the existing preparation of Engliclazide, the research and search of a route which is suitable for industrial production and has the advantages of mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost is the problem to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art, and solve the problems that dangerous chemicals n-butyllithium and low temperature are needed for side chain reactions of sugar and aryl, and the control is difficult, the invention provides a novel Engliflozin intermediate compound and a novel method for preparing Engliflozin by using the novel intermediate, and the target product prepared by the method has the characteristics of higher purity and yield, mild reaction conditions, simple and convenient operation process and lower production cost.
The specific technical content of the invention is as follows:
in a first aspect, the present invention provides a novel englitjing intermediate compound having the structure shown in formula II:
Figure BDA0003396836720000032
the second aspect of the invention provides a preparation method of the englitjing intermediate compound II: the preparation method of the englitjing intermediate compound II comprises the following steps: adding the compound SM-1 and the compound SM-2 into the organic solvent A, adding a zinc and nickel catalyst under stirring, adding a ligand and magnesium chloride under ice bath condition, stirring for reaction until the reaction is finished, and performing post-treatment on the reaction to obtain a compound II:
Figure BDA0003396836720000033
preferably, the organic solvent A is selected from one or a combination of tetrahydrofuran, acetonitrile, toluene and N, N-dimethylformamide.
Preferably, the zinc catalyst is selected from one of metallic zinc, zinc chloride and zinc sulfite.
Preferably, the nickel catalyst is selected from one of bis (1, 5-cyclooctadiene) nickel, nickel (II) acetylacetonate, nickel chloride, nickel (II) perchlorate hydrate, wherein bis (1, 5-cyclooctadiene) nickel is particularly preferred.
Preferably, the ligand is selected from one of 2,2 '-bipyridine, 1, 10-phenanthroline, 4-dimethylaminopyridine, pyridine, wherein 2,2' -bipyridine is particularly preferred.
Preferably, the compound SM-1, compound SM-2, zinc catalyst, nickel catalyst, ligand and magnesium chloride are added in the following molar ratio: 1.0:1.0 to 2.0:2.5 to 3.5:0.1 to 0.8:0.1 to 0.8:1.0 to 2.0, with 1.0:1.5:3.0:0.2:0.2:1.2 being particularly preferred.
In a preferred scheme, after the reaction is finished, the post-treatment is required, and the specific steps are as follows: after the reaction, the reaction solution was filtered through celite, water and methylene chloride were added to the filtrate, the organic layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give compound II.
In a third aspect, the present invention provides a process for the preparation of englitjing gateway using the novel intermediate compound II:
Figure BDA0003396836720000041
a method for preparing tenagliflozin, comprising the following steps:
step 1: adding a compound II and sodium methoxide into a single-neck flask at room temperature, adding the mixture into methanol, and carrying out reflux reaction at a controlled temperature until the reaction is finished to obtain a compound III;
step 2: adding a mixed solvent of the compound III and dried dichloromethane/acetonitrile into a single-neck flask, adding ethyl silane and boron fluoride diethyl ether complex at the temperature of-10 ℃, heating to the temperature of 0 ℃, and stirring until the reaction is finished to obtain the engagliflozin.
Preferably, the molar ratio of the compound II to the sodium methoxide in the step 1 is as follows: 1:5.0.
Preferably, the molar ratio of the compound III, the ethylsilane and the fluorinated boron diethyl ether complex in the step 2 is as follows: 1.0:4.0:3.0.
In a preferred scheme, after the reaction is finished, the post-treatment is required, and the specific steps of the step 1 are as follows: after the reaction, an acidic resin was added to adjust the pH to 2, the mixture was filtered, the resin was distilled off with anhydrous methanol, the solvent was distilled off from the filtrate under reduced pressure, and the crude product was recrystallized from methanol/methylene chloride to give compound III.
The post-treatment specific steps of the step 2 are as follows: after the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove the drying agent, concentrating under reduced pressure, evaporating to remove the solvent, and recrystallizing the crude product with a mixed solution of ethanol and ethyl acetate (volume ratio 1:1) to obtain the engagliflozin.
Compared with the prior art, the invention has the technical effects that:
1. provides a new intermediate compound of the enggliflozin, and simultaneously provides a simple and efficient method for preparing the enggliflozin by using the new intermediate, the whole synthesis method has simple and convenient operation, avoids the use of dangerous chemicals such as n-butyl and the like, and has high reaction yield;
2. the process can solve the problems of low reaction temperature and difficult control of sugar and side chains, and effectively remove alpha-configuration impurities in the product;
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 structure of the compound obtained by the invention is confirmed:
Figure BDA0003396836720000051
HPLC peak area normalization method:
chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 230nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 10.5min.
High resolution mass spectrum of compound II: ESI-HRMS m/z=818.4105 [ M+H ]] + ,mp 356～359℃， 1 H-NMR(400MHz,DMSO-d 6 )δ:7.48(d,1H),7.28(d,2H),7.25(s,1H),7.19(d,1H),6.89(d,2H),5.95(dd,1H),5.86(s,1H),5.74(dd,1H),5.47(d,1H),5.26(dd,1H),4.78(d,1H),4.32(d,1H),4.25(d,1H),4.07(d,1H),4.05(m,1H),4.00(d,1H),3.80(t,1H),3.70(t,1H),3.30(s,3H),2.36(dt,1H),2.11(dt,1H),1.27(s,36H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:177.1,154.9,138.9.137.7,137.1,130.6,129.6,129.1,128.9,128.8,125.4,115.0,114.9,84.9,80.8,80.6,79.6,75.0,74.9,70.2,69.4,67.5,63.6,57.6,38.7,32.2,27.4。
Figure BDA0003396836720000061
Characterization of compound III:
HPLC peak area normalization method:
chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 230nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 20.5min.
ESI-HRMS(m/z)：503.9376[M+Na] + . 1 H-NMR(400MHz,DMSO-d 6 )δ:77.48(d,1H),7.28(d,2H),7.25(s,1H),7.19(d,1H),6.89(d,2H),5.86(s,1H),4.88(d,1H),4.51(br,2H),4.37(br,1H),4.25(d,1H),4.08(d,1H),4.05(m,1H),4.00(d,1H),3.94(br,1H),3.80(t,1H),3.70(m,2H),3.60(m,2H),3.57(d,1H),3.51(d,1H),3.30(s,3H),2.36(dt,1H),2.11(dt,1H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:154.9,138.9.137.7,137.1,130.6,129.6,129.1,128.9,128.8,125.4,115.0,114.9,84.9,84.8,80.8,79.6,78.7,75.0,71.5,70.2,67.5,62.2,57.6,32.2.
HPLC peak area normalization method:
Figure BDA0003396836720000071
HPLC peak area normalization method:
chromatographic column: YMC-Triart C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: a: acetonitrile, B: gradient elution with water (0.fwdarw.10 min: A40%, 10.fwdarw.30 min: A40% -90%);
column temperature: 35 ℃;
detection wavelength: 224nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 16.80min.
ESI-HRMS:m/z＝451.9212[M+H] + ,mp149～152℃, 1 H NMR(400MHz,MeOD)δ:7.36(d,2H),7.28(dd,1H),7.13(d,2H),6.81-6.89(m,2H),4.87-4.94(m,1H),4.11(d,1H),4.00(d,1H),3.95(ddd,5H),3.68(dd,1H),3.36-3.53(m,3H),3.24-3.35(m,2H),2.18(dtd,1H),1.98-2.13(m,1H)。 13 C NMR(400MHz,MeOD)δ:154.9，143.2，137.7，133.1，130.7，130.6，129.1，128.9，128.8，125.4，115.0，114.9，84.8，80.8，79.6，78.7，75.0，71.5，70.2，67.5，62.2，36.5，32.2.
Preparation of Compound II
Example 1
The compound SM-1 (44.40 g,0.1 mol), the compound SM-2 (86.73 g,0.15 mol) were added to tetrahydrofuran (300 ml), zinc (19.62 g,0.3 mol), bis (1, 5-cyclooctadiene) nickel (5.50 g,0.02 mol), 2' -bipyridine (3.12 g,0.02 mol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, and the mixture was reacted with an ice bath under argon atmosphere for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by decompression concentration, and the compound II is obtained with the yield of 98.4 percent and the HPLC purity of 99.92 percent.
Example 2
Compound SM-1 (44.40 g,0.1 mol), compound SM-2 (57.82 g,0.10 mol) were added to acetonitrile (300 ml), zinc chloride (40.89 g,0.2 mol), bis (1, 5-cyclooctadiene) nickel (5.50 g,0.02 mol), 2' -bipyridine (3.12 g,0.02 mol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, and the reaction mixture was stirred with celite, water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give compound II in 94.5% yield and 99.62% purity by HPLC.
Example 3
The compound SM-1 (44.40 g,0.1 mol), the compound SM-2 (115.64 g,0.20 mol) were added to toluene (360 ml), zinc sulfite (54.44 g,0.2 mol), bis (1, 5-cyclooctadiene) nickel (5.50 g,0.02 mol), 2' -bipyridine (3.12 g,0.02 mol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, and the mixture was reacted with an ice bath under argon atmosphere for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 94.8 percent and the HPLC purity of 99.48 percent.
Example 4
Compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol) were added to tetrahydrofuran (200 ml), zinc (16.35 g,0.25 mol), nickel (II) acetylacetonate (5.14 g,0.02 mol), 2' -bipyridine (3.12 g,0.02 mol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, and the reaction mixture was ice-bath reacted for 3 hours under the protection of argon, after the reaction was completed, the reaction mixture was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 94.5% and the HPLC purity of 99.45%.
Example 5
The compound SM-1 (44.40 g,0.1 mol), the compound SM-2 (86.73 g,0.15 mol) were added to tetrahydrofuran (200 ml), zinc (22.89 g,0.35 mol), nickel chloride (2.60 g,0.02 mol), 2' -bipyridine (3.12 g,0.02 mol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, the reaction mixture was ice-bath reacted for 3 hours under the protection of argon, after the reaction was completed, the reaction mixture was filtered through celite, water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the compound II is obtained with the yield of 95.5 percent and the HPLC purity of 99.32 percent.
Example 6
To tetrahydrofuran (300 ml) was added compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol), zinc (19.62 g,0.3 mol), bis (1, 5-cyclooctadiene) nickel (2.75 g,0.01 mol), 2' -bipyridine (1.56 g,0.01 mol), magnesium chloride (11.43 g,0.12 mol) under argon, and an ice bath was used for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give compound II in 94.1% yield and 99.61% purity by HPLC.
Example 7
To tetrahydrofuran (300 ml) was added compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol), zinc (19.62 g,0.3 mol), bis (1, 5-cyclooctadiene) nickel (22.0 g,0.08 mol), 2' -bipyridine (12.50 g,0.08 mol), magnesium chloride (11.43 g,0.12 mol) under argon, and an ice bath was used for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 95.2 percent and the HPLC purity of 99.48 percent.
Example 8
To tetrahydrofuran (300 ml) was added compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol), zinc (19.62 g,0.3 mol), bis (1, 5-cyclooctadiene) nickel (5.50 g,0.02 mol), 1, 10-phenanthroline (3.6 g,0.02 mol), magnesium chloride (9.52 g,0.1 mol) under argon, and an ice bath was used for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give compound II in 95.4% yield and 99.72% purity by HPLC.
Example 9
To tetrahydrofuran (300 ml) was added compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol), zinc (19.62 g,0.3 mol), bis (1, 5-cyclooctadiene) nickel (5.50 g,0.02 mol), 4-dimethylaminopyridine (2.45 g,0.02 mol), magnesium chloride (19.04 g,0.2 mol) under argon, and an ice bath was added, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give compound II in 94.3% yield and 99.51% purity by HPLC.
Example 10
Compound SM-1 (44.40 g,0.1 mol), compound SM-2 (86.73 g,0.15 mol) were added to tetrahydrofuran (300 ml), zinc (13.08 g,0.2 mol), bis (1, 5-cyclooctadiene) nickel (2.20 g,8 mmol), 2' -bipyridine (1.25 g,8 mmol), magnesium chloride (11.43 g,0.12 mol) were added under stirring, and the reaction mixture was ice-bath reacted for 3 hours under argon, after the completion of the reaction, the reaction mixture was filtered through celite, water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by concentration under reduced pressure, and the compound II is obtained with the yield of 88.6% and the HPLC purity of 98.87%.
Example 11
To tetrahydrofuran (400 ml) was added compound SM-1 (44.40 g,0.1 mol), compound SM-2 (127.21 g,0.22 mol), zinc (24.20 g,0.37 mol), bis (1, 5-cyclooctadiene) nickel (2.75 g,0.1 mol), 2' -bipyridine (1.56 g,0.1 mol), magnesium chloride (20.95 g,0.22 mol) under argon, and an ice bath was used for 3 hours, after the reaction was completed, the reaction solution was filtered through celite, and water (100 ml) and methylene chloride (150 ml) were added to the filtrate, and the organic phase was washed once with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 90.6 percent and the HPLC purity of 98.54 percent.
Preparation of Compound III
Example 12
To a single-necked flask, compound II (163.48 g,0.20 mol), sodium methoxide (54.02 g,1.0 mol) and anhydrous methanol (400 mL) were added, and after the reaction was completed under reflux at 65℃for 4 hours under nitrogen protection, an acidic resin was added to adjust the pH to 2, the filtration was carried out, the resin was distilled off under reduced pressure with anhydrous methanol (60 mL. Times.3), the solvent was distilled off from the filtrate, and the crude product was recrystallized from methanol/dichloromethane to give Compound III in a yield of 98.9% and an HPLC purity of 99.89%.
Preparation of Engliflozin
Example 13
To a single vial was added compound III (48.09 g,0.1 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Dissolving with stirring (300 mL) =1:1), cooling to-10deg.C, adding ethyl silane (23.26 g,0.2 mol), boron trifluoride diethyl etherate (21.29 g,0.15 mol) in sequence, slowly raising to 0deg.C, and reacting at constant temperature for 5 hours. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (450 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (400 mL. Times.3), the organic phases were combined, each of the organic phases was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 99.5 percent and the HPLC purity of 99.98 percent.

Claims (10)

1. An englitjing intermediate compound is characterized in that the structure of the englitjing intermediate compound is shown as a formula II:
Figure FDA0003396836710000011
2. a process for the preparation of the engagliflozin intermediate compound II of claim 1, comprising the steps of: adding the compound SM-1 and the compound SM-2 into the organic solvent A, adding zinc and nickel catalysts under stirring, adding ligands and magnesium chloride under ice bath condition, stirring and reacting until the reaction is finished, and obtaining the compound II through post-treatment, wherein the synthetic route is as follows:
Figure FDA0003396836710000012
3. the preparation method according to claim 2, wherein the organic solvent A is selected from one of tetrahydrofuran, acetonitrile, toluene and N, N-dimethylformamide.
4. The method according to claim 2, wherein the zinc catalyst is one selected from the group consisting of metallic zinc, zinc chloride, and zinc sulfite.
5. The preparation method according to claim 2, wherein the nickel catalyst is selected from one of bis (1, 5-cyclooctadiene) nickel, nickel (II) acetylacetonate, nickel chloride, nickel (II) perchlorate hydrate.
6. The preparation method according to claim 2, wherein the ligand is one selected from the group consisting of 2,2' -bipyridine, 1, 10-phenanthroline, 4-dimethylaminopyridine and pyridine.
7. The preparation method according to claim 2, wherein the compound SM-1, the compound SM-2, the zinc catalyst, the nickel catalyst, the ligand and the magnesium chloride are added in the following molar ratio: 1.0:1.0-2.0:2.5-3.5:0.1-0.8:0.1-0.8:1.0-2.0.
8. Use of an englitazone intermediate compound of claim 1 for the preparation of englitazone.
9. Use of an england intermediate compound of claim 8 for the preparation of england, characterized in that the preparation process comprises the steps of:
step 1: adding the compound II and sodium methoxide into methanol at room temperature, and carrying out reflux reaction at a controlled temperature until the reaction is finished to obtain a compound III;
step 2: adding a mixed solvent of the compound III and dried dichloromethane/acetonitrile into a single-neck flask, adding ethyl silane and boron fluoride diethyl ether complex at the temperature of-10 ℃, heating to the temperature of 0 ℃, and stirring until the reaction is finished to obtain the englitjing:
Figure FDA0003396836710000021
10. the use according to claim 9, wherein the compound II, sodium methoxide in step 1 is fed in a molar ratio of: 1:5.0; the feeding mole ratio of the compound III, the ethylsilane and the boron fluoride diethyl ether complex in the step 2 is as follows: 1.0:4.0:3.0.
CN202111517087.6A 2021-12-07 2021-12-07 Engliflozin intermediate compound and preparation method thereof Pending CN116239582A (en)

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