CN116239583A - Synthetic method of enggliflozin - Google Patents
Synthetic method of enggliflozin Download PDFInfo
- Publication number
- CN116239583A CN116239583A CN202111517492.8A CN202111517492A CN116239583A CN 116239583 A CN116239583 A CN 116239583A CN 202111517492 A CN202111517492 A CN 202111517492A CN 116239583 A CN116239583 A CN 116239583A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- mol
- added
- cobalt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—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
- 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
- C07D407/12—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 linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of englitazone. According to the invention, cobalt dibromide complex and zinc powder are used as catalysts, and ethyl chloroformate is used as a bridge to realize carbon-carbon bond construction of aryl bromide, so that synthesis of an important intermediate II of Engliclazide is realized, and the intermediate is further reduced and deprotected to prepare Engliclazide.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of englitazone.
Background
Engliflozin (empagliflozin), a sodium glucose cotransporter 2 (SGLT-2) inhibitor developed by the company Boringer GmbH, germany and Gift GmbH, under the chemical name (2S, 3R,4R,5S, 6R) -2- [3- [4- [ (S) -tetrahydrofuran-3-yloxy ] benzyl ] -4-chlorophenyl ] -6-hydroxymethylepoxyhexane-3, 4, 5-triol, molecular weight: 450.91, CAS registry number 864070-44-0, having the following structural formula:
the prior reported process for synthesizing the englitazone mainly comprises the steps of preparing aryl nucleophilic reagent, and then reacting the nucleophilic reagent with glycosyl side chains.
For example, chinese patent application CN105399735 uses-iodine-2-chlorobenzoic acid as raw material, and adopts multi-step reaction to obtain side chain compound, and makes side chain and glycosyl undergo the process of coupling reaction under the catalysis of n-butyllithium and zinc bromide-lithium bromide, and the obtained product can be deprotected so as to obtain the invented Engliflozin.
The process uses dangerous n-butyllithium when linking the glycosyl group and the side chain, and is not suitable for industrial mass production.
U.S. Pat. No. 3,182 discloses a method for preparing the englitz-wire by using a chiral hydroxyl compound which is prepared by carrying out nucleophilic addition reaction on a side chain compound and glycosyl ketone after carrying out Grignard reagent exchange reaction on isopropyl magnesium chloride/lithium chloride, and carrying out reaction on the side chain compound under the condition of hydrochloric acid-methanol solution, and removing methoxy group under the action of triethylsilane-aluminum trichloride to obtain the englitz-wire:
although the process avoids the use of n-butyllithium, the addition reaction generates redundant chiral hydroxyl, and the removal of the hydroxyl is troublesome and is not suitable for industrial mass production.
In view of the problems in the existing preparation of the side chain and glycosyl reaction of the engagliflozin, the research and the search of a reaction condition are mild, the operation process is simple and convenient, the product yield is high, the purity is high, and the production cost is low, so that the route suitable for the industrial production of glycosyl and side chain reaction is the problem to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel method for preparing the Engliflozin, which aims to solve the problems that dangerous chemicals such as n-butyllithium are needed for the reaction of side chains and glycosyl groups in the process of preparing the Engliflozin, the reaction steps are long and the yield is low, and has the characteristics of higher purity and yield, mild reaction conditions, simple operation process and lower production cost, and the process is more suitable for industrial production.
The specific technical content of the invention is as follows:
the preparation process of enggliflozin includes the following steps:
the preparation method of the englitjing specifically comprises the following steps:
step 1: adding a catalyst, zinc powder and trifluoroacetic acid into an organic solvent, carrying out reflux reaction until a reaction liquid turns purple, cooling the reaction liquid to room temperature, adding chloropropene, ethyl chloroformate, a compound SM-1 and a compound SM-2, carrying out room temperature reaction until the reaction is finished, and carrying out post-treatment to obtain a compound II;
step 2: adding a mixed solvent of the compound II 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 organic solvent in step 1 is selected from one or a combination of acetonitrile, tetrahydrofuran and toluene.
Preferably, the catalyst in the step 1 is selected from one of cobalt 2, 2-bipyridine dibromide, cobalt bis (triphenylphosphine) dibromide and cobalt 1, 10-phenanthroline dibromide.
Preferably, the molar ratios of ethyl chloroformate, compound SM-2, compound SM-1, catalyst, zinc powder and chloropropene in the step 1 are as follows: 1.0:1.0 to 2.0:1.0 to 2.0:0.08 to 0.15:7.0 to 10.0:0.2 to 0.5, with 1.0:1.25:1.25:0.1:8.0:0.3 being particularly preferred.
Preferably, the molar ratio of the compound II, the ethylsilane and the boron fluoride 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, post-treatment is required, and step 1 specifically comprises the following steps: after the reaction, the diatomite is filtered, the filter cake is washed by dichloromethane, the filtrate is diluted by 1M hydrochloric acid aqueous solution, the organic phase is separated, the aqueous phase is extracted by dichloromethane, the organic phases are combined, the organic phase is washed by saturated saline, dried by anhydrous sodium sulfate, filtered, and the filtrate is distilled under reduced pressure to remove the solvent to obtain the compound II.
The post-treatment of the step 2 is as follows: after completion of this, 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. the invention provides a novel method for efficiently synthesizing an Englibenclamide intermediate compound II, which takes cobalt complex and zinc as catalysts, and has high reaction selectivity, mild conditions and high yield;
2. the process can solve the problem of using n-butyl lithium, has short whole synthetic route and simple operation, and is more suitable for industrial mass production;
3. the Engliflozin prepared by the method can be prepared by reduction and deprotection of the Engliflozin purifying compound II, and the synthesis method is simple and convenient and does not generate addition impurities.
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:
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: 220nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 13.6min.
ESI-HRMS:m/z＝826.3672[M+Na] + ,mp 234～236℃， 1 H-NMR(400MHz,DMSO-d 6 )δ:7.73(d,2H),7.62(s,1H),7.55(d,1H),7.41(d,1H),7.03(d,2H),5.95(dd,1H),5.74(dd,1H),5.47(d,1H),5.26(dd,1H),4.78(dt,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),2.36(dt,1H),2.11(dt,1H),1.278(s,36H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:196.3,177.7,177.1,161.1,136.9,136.5,136.2,131.6,131.0,130.9,130.8,130.0,127.2,114.1,114.0,80.8,80.6,79.6,74.9,74.7,70.2,69.4,67.5,63.6,39.0,38.7,32.2,27.4.
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: 10ul;
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
To a single flask were added cobalt 2, 2-bipyridine dibromide (9.30 g,0.02 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), vigorously stirred, the reaction mixture was warmed to reflux, the reaction mixture turned from white to purple, chloropropene (4.59 g,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, the reaction was carried out at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added, and the reaction was carried out at room temperature for 5 hours. After the reaction, the kieselguhr was filtered, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 98.8% and an HPLC purity of 99.90%.
Example 2
To a single flask was added cobalt bis (triphenylphosphine) dibromide (14.83 g,0.02 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction mixture was warmed to reflux with vigorous stirring, turned from white to purple, chloropropene (4.59 g,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the reaction was continued at constant temperature for 1 hour, followed by the addition of compound SM-1 (137.64 g,0.20 mol) and compound SM-2 (48.40 g,0.20 mol) and reaction was continued at room temperature for 5 hours. After the reaction, the mixture was filtered through suction with celite, the cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound II in a yield of 94.1% and HPLC purity of 99.62%.
Example 3
To a single-necked flask, 1, 10-phenanthroline cobalt dibromide (7.80 g,0.02 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (400 mL) were added, and the mixture was stirred vigorously, heated to reflux, the reaction mixture was changed from white to purple, chloropropene (4.59 g,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the mixture was allowed to react at constant temperature for 1 hour, and compound SM-1 (275.28 g,0.40 mol) and compound SM-2 (96.80 g,0.40 mol) were added in this order, and reacted at room temperature for 5 hours. After the reaction, the kieselguhr was filtered, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 95.1% and an HPLC purity of 99.50%.
Example 4
To a single flask was added cobalt 2, 2-bipyridine dibromide (7.44 g,0.016 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and tetrahydrofuran (300 mL), and the reaction mixture was warmed to reflux with vigorous stirring, the reaction mixture was changed from white to purple, chloropropene (4.59 g,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the reaction was continued at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were added in this order, and the reaction was continued at room temperature for 5 hours. After the reaction, diatomaceous earth was filtered off with suction, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give compound II in a yield of 94.6% and an HPLC purity of 99.41%.
Example 5
To a single flask was added cobalt 2, 2-bipyridine dibromide (13.95 g,0.03 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and toluene (300 mL), vigorously stirred, the reaction mixture was warmed to reflux, the reaction mixture turned from white to purple, chloropropene (4.59 g,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, the reaction was carried out at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added, and the reaction was carried out at room temperature for 5 hours. After the reaction, the kieselguhr was filtered, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 95.6% and an HPLC purity of 99.42%.
Example 6
To a single-necked flask, 2-bipyridine cobalt dibromide (9.30 g,0.02 mol), zinc powder (91.56 g,1.40 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL) were added, and the mixture was vigorously stirred, heated to reflux, the reaction mixture was changed from white to purple, chloropropene (50 mL,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the reaction was continued at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added, and the reaction was continued at room temperature for 5 hours. After the reaction, the kieselguhr was filtered by suction, the filter cake was washed with methylene chloride (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 94.1% and an HPLC purity of 99.59%.
Example 7
To a single-necked flask, 2-bipyridine cobalt dibromide (9.30 g,0.02 mol), zinc powder (130.8 g,2.0 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL) were added, and the mixture was stirred vigorously, warmed to reflux, the reaction mixture turned from white to purple, when the reaction system was allowed to react at room temperature, chloropropene (50 mL,0.06 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, the reaction was carried out at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added and the reaction was carried out at room temperature for 5 hours. After the reaction, the kieselguhr was filtered, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 95.1% and an HPLC purity of 99.50%.
Example 8
To a single-necked flask, 2-bipyridine cobalt dibromide (9.30 g,0.02 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL) were added, and vigorously stirred, the reaction mixture was warmed to reflux, the reaction mixture turned from white to purple, chloropropene (3.06 g,0.04 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the reaction was carried out at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added, and the reaction was carried out at room temperature for 5 hours. After the reaction, the kieselguhr was filtered by suction, the filter cake was washed with methylene chloride (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 95.5% and an HPLC purity of 99.73%.
Example 9
To a single-necked flask, 2-bipyridine cobalt dibromide (9.30 g,0.02 mol), zinc powder (104 g,1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL) were added, and vigorously stirred, the reaction mixture was warmed to reflux, the reaction mixture turned from white to purple, chloropropene (7.65 g,0.1 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the reaction was carried out at constant temperature for 1 hour, and compound SM-1 (171.52 g,0.25 mol) and compound SM-2 (60.78 g,0.25 mol) were sequentially added, and the reaction was carried out at room temperature for 5 hours. After the reaction, the kieselguhr was filtered under suction, the filter cake was washed with methylene chloride (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 94.3% and an HPLC purity of 99.52%.
Example 10
To a single-necked flask, 2-bipyridine cobalt dibromide (6.51 g,0.014 mol), zinc powder (78.48 g,1.20 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL) were added, and the mixture was vigorously stirred, heated to reflux, the reaction mixture was changed from white to purple, chloropropene (1.53 g,0.02 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the mixture was allowed to react at constant temperature for 1 hour, and compound SM-1 (137.64 g,0.2 mol) and compound SM-2 (48.40 g,0.2 mol) were sequentially added, and reacted at room temperature for 5 hours. After the reaction, the kieselguhr was filtered, the filter cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure to give Compound II in a yield of 88.0% and an HPLC purity of 98.84%.
Example 11
To a single-necked flask, 2-bipyridine cobalt dibromide (16.74 g,0.036 mol), zinc powder (156.96 g,2.40 mol), trifluoroacetic acid (5 mL) and acetonitrile (600 mL) were added, and the mixture was vigorously stirred, heated to reflux, the reaction mixture was changed from white to purple, chloropropene (10.71 g,0.14 mol) was added, ethyl chloroformate (200 mL,0.20 mol) was added, and the mixture was allowed to react at constant temperature for 1 hour, and compound SM-1 (302.81 g,0.44 mol) and compound SM-2 (106.48 g,0.44 mol) were sequentially added, and the mixture was allowed to react at room temperature for 5 hours. After the reaction, the mixture was filtered through suction with celite, the cake was washed with dichloromethane (50 mL. Times.3), the filtrate was diluted with 1mol/L aqueous hydrochloric acid (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent to give Compound II in 89.4% yield and 98.24% HPLC purity.
Preparation of Engliflozin
To a single vial was added compound II (80.14 g,0.10 mol) and dried dichloromethane/acetonitrile (v: v=1:1, 400 mL) with stirring to dissolve, cooled to-10 ℃, ethyl silane (23.26 g,0.20 mol), boron trifluoride diethyl etherate (21.29 g,0.15 mol) were added in sequence, and the mixture was slowly warmed to 0 ℃ and reacted at constant temperature for 5 hours. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (400 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. Filtering to remove the drying agent, concentrating under reduced pressure, and evaporating to remove the solvent to obtain off-white solid which is directly used as the next step; the above off-white solid, methanesulfonic acid (1.44 g,15 mmol) and anhydrous methanol (75 mL) were added to a single-necked flask and dissolved with stirring, and reacted at room temperature for 2 hours. After the reaction, sodium bicarbonate (1.3 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (200 ml, volume ratio 1:1) to give engagliflozin, yield 98.5%, and HPLC purity 99.98%.
Claims (5)
1. The synthesis method of the englitjing is characterized by comprising the following steps of:
step 1: adding a catalyst, zinc powder and trifluoroacetic acid into an organic solvent, carrying out reflux reaction until a reaction liquid turns purple, cooling the reaction liquid to room temperature, adding chloropropene, ethyl chloroformate, a compound SM-1 and a compound SM-2, carrying out room temperature reaction until the reaction is finished, and carrying out post-treatment to obtain a compound II;
step 2: adding a mixed solvent of a compound II 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 englitazone, wherein the synthetic route is as follows:
2. the method according to claim 1, wherein the organic solvent in step 1 is selected from one or a combination of acetonitrile, tetrahydrofuran, toluene.
3. The method of claim 1, wherein the catalyst of step 1 is selected from one of cobalt 2, 2-bipyridine dibromide, cobalt bis (triphenylphosphine) dibromide, and cobalt 1, 10-phenanthroline dibromide.
4. The synthesis method according to claim 1, wherein the molar ratio of ethyl chloroformate, compound SM-2, compound SM-1, catalyst, zinc powder and chloropropene in step 1 is: 1.0:1.0-2.0:1.0-2.0:0.08-0.15:7.0-10.0:0.2-0.5.
5. The synthesis method according to claim 1, wherein the compound II, ethyl silane, and boron fluoride diethyl ether complex in step 2 are added in a molar ratio of: 1.0:4.0:3.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111517492.8A CN116239583A (en) | 2021-12-08 | 2021-12-08 | Synthetic method of enggliflozin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111517492.8A CN116239583A (en) | 2021-12-08 | 2021-12-08 | Synthetic method of enggliflozin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116239583A true CN116239583A (en) | 2023-06-09 |
Family
ID=86630131
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111517492.8A Pending CN116239583A (en) | 2021-12-08 | 2021-12-08 | Synthetic method of enggliflozin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116239583A (en) |
-
2021
- 2021-12-08 CN CN202111517492.8A patent/CN116239583A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113549042B (en) | Preparation method of dapagliflozin | |
| CN107556302B (en) | Method for preparing empagliflozin | |
| CN112574163B (en) | Method for synthesizing Brazilin natural product (+) -Brazilin | |
| CN112608296B (en) | Synthesis method of Brazilane natural product Brazilane | |
| CN108178770B (en) | Method for synthesizing α -amino boron compound | |
| CN102391325A (en) | Method for preparing 4,6-dibenzyl 2,3-unsaturated glucoside | |
| CN108264454B (en) | Preparation method of phloroglucinol derivative and intermediate | |
| CN110078622B (en) | Synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate | |
| CN116239583A (en) | Synthetic method of enggliflozin | |
| CN108530402B (en) | Preparation method of (R) -3-propyl-gamma-butyrolactone | |
| CN107129515B (en) | Novel method for synthesizing natural product Cyanolide A analogue | |
| CN115108937A (en) | Synthesis method of alpha-azidoketone containing three-level stereocenter | |
| CN109369678B (en) | Synthetic method of natural product isomer (-) -6-epi-Poranteridine | |
| CN110776488A (en) | Method for synthesizing (-) -Brazilin | |
| CN113461643A (en) | Synthesis method of 4-methylbenzenesulfonic acid [ (3-fluoro-oxetan-3-yl) methyl ] ester | |
| CN112225769A (en) | Method for synthesizing and purifying tulathromycin impurity E | |
| CN115197281B (en) | Preparation method of etoposide intermediate | |
| CN116239582A (en) | Engliflozin intermediate compound and preparation method thereof | |
| CN114478407B (en) | Preparation method and application of chiral homopiperazine and derivatives thereof | |
| CN111138293B (en) | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor | |
| CN113979835B (en) | Synthesis method of pazopanib trimer impurity intermediate | |
| CN112794837B (en) | Synthesis method of heterochroman compound | |
| CN109336899B (en) | Method for synthesizing natural product gamma-lycorane | |
| CN112645902B (en) | Synthesis method of 1- (4-bromophenyl) piperidine | |
| KR102381035B1 (en) | Novel Synthtic Method for gaylussacin derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |