CN105294624A - Preparation method for dapagliflozin - Google Patents
Preparation method for dapagliflozin Download PDFInfo
- Publication number
- CN105294624A CN105294624A CN201510786909.9A CN201510786909A CN105294624A CN 105294624 A CN105294624 A CN 105294624A CN 201510786909 A CN201510786909 A CN 201510786909A CN 105294624 A CN105294624 A CN 105294624A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- chloride
- catalyzer
- reaction
- 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.)
- Granted
Links
- 0 CCNC1=CCC(CC2=C(*)CCC(C(CC3O)OC(C*)[C@]3O)=C2)C=C1 Chemical compound CCNC1=CCC(CC2=C(*)CCC(C(CC3O)OC(C*)[C@]3O)=C2)C=C1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
Abstract
The invention belongs to the field of medicine chemical industry, and concretely relates to a preparation method for dapagliflozin. 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl hydroxide is taken as a raw material and is subjected to a sulfonylation reaction, a nucleophilic substitution reaction and a acetyl removal reaction, so that dapagliflozin is obtained. The preparation method possesses the advantages of mild reaction conditions, simple and reasonable technological process, short reaction time, simple post-processing, high product quality, high yield and the like.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the preparation method that a kind of Da Gelie is clean.
Background technology
Clean (dapagliflozin, the ForxigaTM) chemical name of Da Gelie is (2S, 3R, 4R, 5S, 6R)-2-[3-(4-ethoxyl phenenyl)-4-chloro-phenyl-]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol.It is a kind of novel antidiabetic medicine developed jointly by Bristol Myers Squibb and Astrazeneca AB, on November 12nd, 2012 by European drug administration (EMA) approval listing, be the 1st and get permission to go on the market and be used for the treatment of the SGLT2 inhibitor of diabetes B.FDA announced on January 8th, 2014, ratified treatment Da Gelie being used for only diabetes B, required that manufacturer studies after carrying out listing with regard to medicine relevant risk simultaneously.
Adult every day of normal renal function, most glucose was heavily absorbed at uriniferous tubules probably through the glucose of glomerular filtration 180g, and this process is realized by sodium glucose co-transporter 2 white (SGLTs).SGLT2 is the transport vehicle of a kind of low-affinity, heavy body, at uriniferous tubules proximal convoluted tubule cell brush border nearly S1 section specifically expressing, has mediated the heavily absorption that 90% filters glucose.The clean selectivity of Da Gelie and potent suppress SGLT2, block proximal convoluted tubule to the heavily absorption of glucose, increase the excretion of glucose in urine, thus reduce blood sugar, this hypoglycemic mechanism does not rely on the effect of Regular Insulin.
The clean structure of Da Gelie is as shown in the formula shown in (formula V):
Da Gelie is clean
Following two kinds are mainly contained about the synthetic route of this formula V in prior art:
(1) international monopoly WO03/099836A1 and J.Med.Chem.2008,51,1145 – 1149 report the clean synthesis technique of Da Gelie.By 2,3,4,6-tetra--O-trimethyl silicon based-that D-Glucose acid lactone must arrive lattice row by steps such as addition, dehydroxylation and upper protections is clean, reaction scheme is as follows:
(2) people such as Lemaire reports by 2; 3; 4; 6-O-tetra-pivaloyl group-alpha-brominated Glucopyranose is starting raw material; important intermediate is obtained, (Org.Lett., Vol.14 through linked reaction; No.6,2012) be hydrolyzed by this intermediate that namely can to obtain Da Gelie clean again.
(3) international monopoly WO2010022313 reports the clean synthesis technique of another Da Gelie.By 2,3,4,6-tetra--O-trimethyl silicon based-D-Glucose acid lactone must arrive lattice by addition, demethoxylation step and arrange clean crude product, then with L-PROLINE eutectic purifying, the cleaner sterling of the Da Gelie that dissociates.
Above three kinds of routes synthesizing Da Gelie clean all have certain disadvantages, as: after (-78 DEG C) carry out linked reaction at low temperatures, add anhydrous methanol process, be converted into methoxy compound (7), then reduce demethoxylated reaction, reaction scheme is longer, technique is loaded down with trivial details, product purity is not high, and route total recovery is low, not easily refines; Employing Gluconolactone is raw material, needs to carry out derivatize to crude product in subsequent purification technique, and derivatize adds the operation steps of reaction, is unfavorable for improving reaction yield; Need the n-Butyl Lithium using high risk; Severe reaction conditions needs-78 DEG C of low temperature, easily produces impurity in reaction process, is unfavorable for that follow-up product is purified; Use zinc bromide water absorbability in synthesis strong especially, be unfavorable for amplifying and operation; Starting material as expensive in 2,3,4,6-O-tetra-pivaloyl group-alpha-brominated Glucopyranose and be not easy obtain; Post-processing step is loaded down with trivial details.Therefore all suitability for industrialized production is unfavorable for a certain extent.
Only also report is had to Da Gelie in other document, such as:
Chinese patent CN104496952A: adopt halogeno-benzene derivative and 2,3,4; 6 ,-four acetoxyl group-α-D-Glucopyranose bromides are raw material, eliminate the reduction reaction in former method and acetylating reaction; shorten reaction process step, improve total recovery.Benzene lithium reagent is prepared into the relatively mild copper lithium reagent of reaction or Grignard reagent intermediate, decrease the generation of by product, purity is increased to 99.93%, impurity all controls below 0.05%, but reaction still uses n-Butyl Lithium, the temperature that reaction needed-40 DEG C is even lower, complex operation step, is unfavorable for suitability for industrialized production.
Chinese patent CN104059041A: with the ALPHA-D-bromo Glucopyranose of hydroxyl protection for starting raw material, the grignard reagent made with halogeno-benzene derivative, carries out being obtained by reacting the clean advanced intermediate of Da Gelie under cobalt catalyst and part exist.This operation is simple, and with low cost, eliminate the reduction reaction in former method and acetylating reaction, shorten reaction process step, reaction conditions is also gentleer, but this reaction yield is the highest just reaches 84%, still has much room for improvement.Find that this advanced intermediate product purity be obtained by reacting is low by test, foreign matter content is high, aftertreatment difficulty.
The present invention adopts 2,3,4,6-α-D-Glucopyranose four acetyl acid esters to be raw material, reacts three reaction process must arrive lattice row only through sulfonylation, nucleophilic substitution reaction, deacetylate.The present invention has reaction conditions gentleness, advantages of simple technological process, and the reaction times is short, aftertreatment is simple, quality product is high, productive rate advantages of higher.
Summary of the invention
The object of the invention is to overcome the defect existed in existing synthetic method, provide a kind of technique simple, production cost is low, product purity and the clean preparation method of the high Da Gelie of yield.
Problem of the present invention solves by the following technical programs:
The preparation method that Da Gelie is clean, is characterized in that it comprises the steps:
A, by chemical compounds I and SULPHURYL CHLORIDE reagent under the effect of medium and catalyzer, carry out sulfonylation, generate Compound II per;
The Grignard reagent Lewis acid of b, Compound II per and compound III is carried out reacting obtained compound IV as catalyzer.
C, compound IV are under the effect of catalysts and solvents, and reflux, carries out deacetylation protection and obtain compound V.
Synthetic route of the present invention is as follows:
Preferably, the SULPHURYL CHLORIDE reagent described in step a is Methanesulfonyl chloride or Tosyl chloride.
Preferably, medium described in step a is Ag
2o, described catalyzer is KI.
Preferably, in step a, the molar mass ratio of each material is n (SULPHURYL CHLORIDE reagent): n (Ag
2o): n (Compound I): n (KI)=1.4:1.5:1.0:0.3.
Preferably, the Grignard reagent of the compound III described in step b is compound III and n-butylmagnesium chloride magnesium or isopropylmagnesium chloride generation permutoid reaction and obtained grignard reagent.
Preferably, the Lewis acid described in step b comprises aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, columbium pentachloride, titanium tetrachloride, tin tetrachloride, preferred tin tetrachloride.
Preferably, the catalyzer described in step c is Dibutyltin oxide, and solvent is methyl alcohol.
Preferably, the catalyzer described in step c is 1:2 with the mole dosage ratio of compound IV.
Preferably, the Heating temperature 90-110 DEG C described in step c.
Relative to prior art, advantage of the present invention is:
(1) of the present inventionly the clean method of Da Gelie is prepared, synthetic route shortens dramatically, only have three steps, simplify operating procedure, reaction conditions is comparatively gentle, aftertreatment is simple and easy to do, the clean purity of the Da Gelie obtained is high, is more suitable for industrialization production requirements, not only saves production time and labour cost, and reduce production cost, increase substantially the yield of reaction.
(2) when preparing compound (IV), this route take first by compound (I) with Ag
2o is medium, and KI is catalyzer, by controlling the amount of each reactive material, carries out sulfonylation, and the alkylsulfonyl in the compound (II) obtained more easily is left away, and improves reaction yield;
(3) in step b, the grignard reagent Lewis acid of Compound II per and compound III is carried out reacting obtained compound IV as catalyzer.Especially adopt anhydrous stannic chloride as catalyzer, the stereoselectivity of reaction is good, and yield reaches 97%.
(4) adopting in step c with Dibutyltin oxide is catalyzer, and the method for methanol as solvent deacetylation protecting group, removes glucosides ethanoyl in a mild condition, and method is simple, and the reaction times is short, and productive rate is high.By controlling reaction solvent, time and the condition such as stable, shortening the reaction times, improve reaction yield.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1: the synthesis of Compound II per
10.12g (90.8mmol) Mscl is dissolved in 250mlCH
2cl
2in, add the Ag of 20.42g (100.5mmol) brand-new
2o, after stirring at room temperature number minute, adds 10.26g (70mmol) Compound I and 3.5g (20.1mmol) KI, stirring at room temperature 6h successively.TLC detection reaction process, reacts complete decompress filter, residue CH
2cl
2(50ml × 3) wash.Filtrate is concentrated into small volume, is separated (V through silica gel column chromatography
sherwood oil: V
ethyl acetatefor 5:1) purifying, obtain 10.77g (60.86mmol) Compound II per, yield 98%, purity 99.9%.
Embodiment 2: the synthesis of Compound II per
10.87g (90.8mmol) Tscl is dissolved in 250mlCH
2cl
2in, add the Ag of 20.42g (100.5mmol) brand-new
2o, after stirring at room temperature number minute, adds 10.26g (70mmol) Compound I and 3.5g (20.1mmol) KI, stirring at room temperature 6h successively.TLC detection reaction process, reacts complete decompress filter, residue CH
2cl
2(50ml × 3) wash.Filtrate is concentrated into small volume, is separated (V through silica gel column chromatography
sherwood oil: V
ethyl acetatefor 5:1) purifying, obtain 20.27g (60.79mmol) Compound II per, yield 97%, purity 99.7%.
Embodiment 3: the synthesis of compound IV
The chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene (40.9g is added in 250mL triangular flask, 150mmol) with tetrahydrofuran (THF) 100mL, stir and be cooled to-5 ~ 0 DEG C, slowly drip n-butylmagnesium chloride magnesium (80mL, 2mol/L), system is at 0 DEG C of insulated and stirred 2h.Add 10.77g (60.86mmol) Compound II per (R=-MS) at the triangular flask of another 300ml, 10.81g (60.94mmol) anhydrous stannic chloride and 100ml2-methyltetrahydrofuran, system is cooled to 5 DEG C.The Grignard reagent of slow dropping above in 250ml bottle, about 40min drips off, and system is risen again to room temperature, insulated and stirred 1h, by 1N aqueous hydrochloric acid cancellation system, organic phase is extracted with ethyl acetate, saturated common salt water washing, concentrated, column chromatography (PE/EA=3/1), obtain compound IV 30.83g (60.65mmol), yield 97%, purity 99.8%.
Embodiment 4: the synthesis of compound IV
The chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene (40.9g is added in 250mL triangular flask, 150mmol) with tetrahydrofuran (THF) 100mL, stir and be cooled to-5 ~ 0 DEG C, slowly drip isopropylmagnesium chloride (80mL, 2mol/L), system is at 0 DEG C of insulated and stirred 2h.Add 20.29g (60.86mmol) Compound II per (R=-TS) at the triangular flask of another 300ml, 10.81g (60.94mmol) anhydrous stannic chloride and 100ml2-methyltetrahydrofuran, system is cooled to 5 DEG C.The Grignard reagent of slow dropping above in 250ml bottle, about 40min drips off, and system is risen again to room temperature, insulated and stirred 1h, by 1N aqueous hydrochloric acid cancellation system, organic phase is extracted with ethyl acetate, saturated common salt water washing, concentrated, column chromatography (PE/EA=3/1), obtain compound IV 30.83g (60.65mmol), yield 97%, purity 99.8%.
Embodiment 5: the synthesis of compound V
1.5g (6.0mmol) Dibutyltin oxide and 6.9g (10.2mmol) compound IV are added in 200ml anhydrous methanol, be heated to 90 DEG C, after backflow 1.8h, filtration under diminished pressure, washing, drying under reduced pressure obtains 4.7g (10.16mmol) compound V, yield 97%, purity 99.2%.
Embodiment 6: the synthesis of compound V
1.5g (6.0mmol) Dibutyltin oxide and 6.9g (10.2mmol) compound IV are added in 200ml anhydrous methanol, be heated to 100 DEG C, after backflow 1.8h, filtration under diminished pressure, washing, drying under reduced pressure obtains 4.8g (10.17mmol) compound V, yield 97.5%, purity 99.7%.
Embodiment 7: the synthesis of compound V
1.5g (6.0mmol) Dibutyltin oxide and 6.9g (10.2mmol) compound IV are added in 200ml anhydrous methanol, be heated to 110 DEG C, after backflow 1.8h, filtration under diminished pressure, washing, drying under reduced pressure obtains 4.7g (10.16mmol) compound V, yield 96.7%, purity 99.4%.
Comparative example 1: the synthesis of compound IV
The chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene (40.9g is added in 250mL triangular flask, 150mmol) with tetrahydrofuran (THF) 100mL, stir and be cooled to-5 ~ 0 DEG C, slowly drip n-butylmagnesium chloride magnesium (80mL, 2mol/L), system is at 0 DEG C of insulated and stirred 2h.10.77g (60.86mmol) Compound II per (R=-MS) is added at the triangular flask of another 300ml, Tetramethyl Ethylene Diamine (10wt%), cobalt dichloride (10wt%) and 100ml2-methyltetrahydrofuran, system is cooled to 0 DEG C.The Grignard reagent of slow dropping above in 250ml bottle, about 30min drips off, and system is risen again to 25 ~ 30 DEG C, insulated and stirred 2h, by 1N aqueous hydrochloric acid cancellation system, organic phase is extracted with ethyl acetate, saturated common salt water washing, concentrated, column chromatography (PE/EA=3/1), obtain compound IV 30.51g (60.1mmol), yield 89%, purity 99.0%.
Comparative example 2: the synthesis of compound IV
The chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene (40.9g is added in 250mL triangular flask, 150mmol) with tetrahydrofuran (THF) 100mL, stir and be cooled to-5 ~ 0 DEG C, slowly drip n-butylmagnesium chloride magnesium (80mL, 2mol/L), system is at 0 DEG C of insulated and stirred 2h.(2R is added at the triangular flask of another 300ml, 3R, 4S, 5R, 6R)-2-(acetyl-o-methyl)-6-bromine tetrahydrochysene-2H-pyrans-3,4,5-triacetyl ester (40.1g, 100mmol), 10.81g (60.94mmol) anhydrous stannic chloride and 100ml2-methyltetrahydrofuran, system is cooled to 5 DEG C.The Grignard reagent of slow dropping above in 250ml bottle, about 40min drips off, and system is risen again to room temperature, insulated and stirred 1h, by 1N aqueous hydrochloric acid cancellation system, organic phase is extracted with ethyl acetate, saturated common salt water washing, concentrated, column chromatography (PE/EA=3/1), obtain compound IV 40.95g (80.6mmol), yield 86%, purity 99.4%.
From embodiment 3-4 and comparative example 1-2, adopt the reaction conditions milder of the compound IV of raw material of the present invention and catalysts gained, reaction yield and purity higher.
Claims (9)
1. the preparation method that Yi Zhong Da Gelie is clean, is characterized in that it comprises the steps:
A, by chemical compounds I and SULPHURYL CHLORIDE reagent under the effect of medium and catalyzer, carry out sulfonylation, generate Compound II per;
The Grignard reagent Lewis acid of b, Compound II per and compound III is carried out reacting obtained compound IV as catalyzer;
C, compound IV are under the effect of catalysts and solvents, and reflux, carries out deacetylation protection and obtain compound V;
Synthetic route of the present invention is as follows:
2. preparation method as claimed in claim 1, is characterized in that: the SULPHURYL CHLORIDE reagent described in step a is Methanesulfonyl chloride or Tosyl chloride.
3. preparation method as claimed in claim 1, is characterized in that: medium described in step a is Ag
2o, described catalyzer is KI.
4. preparation method as claimed in claim 3, is characterized in that: in step a, the molar mass ratio of each material is n (SULPHURYL CHLORIDE reagent): n (Ag
2o): n (Compound I): n (KI)=1.4:1.5:1.0:0.3.
5. preparation method as claimed in claim 1, is characterized in that: the Grignard reagent of the compound III described in step b is compound III and n-butylmagnesium chloride magnesium or isopropylmagnesium chloride generation permutoid reaction and obtained grignard reagent.
6. preparation method as claimed in claim 1, is characterized in that: the Lewis acid described in step b comprises aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, columbium pentachloride, titanium tetrachloride, tin tetrachloride, preferred tin tetrachloride.
7. preparation method as claimed in claim 1, it is characterized in that: the catalyzer described in step c is Dibutyltin oxide, solvent is methyl alcohol.
8. preparation method as claimed in claim 1, is characterized in that: the catalyzer described in step c is 1:2 with the mole dosage ratio of compound IV.
9. preparation method as claimed in claim 1, is characterized in that: the Heating temperature 90-110 DEG C described in step c.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510786909.9A CN105294624B (en) | 2015-11-16 | 2015-11-16 | A kind of preparation method of Dapagliflozin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510786909.9A CN105294624B (en) | 2015-11-16 | 2015-11-16 | A kind of preparation method of Dapagliflozin |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105294624A true CN105294624A (en) | 2016-02-03 |
CN105294624B CN105294624B (en) | 2018-01-12 |
Family
ID=55192540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510786909.9A Active CN105294624B (en) | 2015-11-16 | 2015-11-16 | A kind of preparation method of Dapagliflozin |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105294624B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105859672A (en) * | 2016-04-25 | 2016-08-17 | 中国药科大学 | Synthesis method of dapagliflozin |
CN107304194A (en) * | 2016-04-20 | 2017-10-31 | 扬子江药业集团上海海尼药业有限公司 | The method for preparing Dapagliflozin |
CN108084130A (en) * | 2017-12-15 | 2018-05-29 | 东南大学 | A kind of preparation method of antidiabetic drug Dapagliflozin |
CN108530408A (en) * | 2018-04-13 | 2018-09-14 | 海门慧聚药业有限公司 | The method for preparing Dapagliflozin |
WO2021101003A1 (en) * | 2019-11-22 | 2021-05-27 | 연세대학교 산학협력단 | Method for synthesis of gliflozin by using methanesulfonylation intermediate in continuous reaction process |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011048112A1 (en) * | 2009-10-20 | 2011-04-28 | Novartis Ag | Glycoside derivatives and uses thereof |
WO2012140597A1 (en) * | 2011-04-14 | 2012-10-18 | Novartis Ag | Glycoside derivatives and their uses for the treatment of diabetes |
WO2013068850A2 (en) * | 2011-11-07 | 2013-05-16 | Scinopharm Taiwan, Ltd. | PROCESS FOR THE PREPARATION OF β-C-ARYL GLUCOSIDES |
CN103570510A (en) * | 2012-07-19 | 2014-02-12 | 苏州中科天马肽工程中心有限公司 | One-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane |
CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
CN104086379A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Method for synthesizing forxiga intermediate |
WO2015040571A1 (en) * | 2013-09-23 | 2015-03-26 | Ranbaxy Laboratories Limited | Process for the preparation of dapagliflozin |
CN104478839A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Synthesis method of dapagliflozin |
WO2015044849A1 (en) * | 2013-09-27 | 2015-04-02 | Ranbaxy Laboratories Limited | Process for the purification of dapagliflozin |
CN104496952A (en) * | 2014-11-28 | 2015-04-08 | 深圳翰宇药业股份有限公司 | Synthesis method of dapagliflozin |
CN104529970A (en) * | 2015-01-08 | 2015-04-22 | 江苏联环药业股份有限公司 | Method for preparing Dapagliflozin |
WO2015063726A1 (en) * | 2013-10-31 | 2015-05-07 | Ranbaxy Laboratories Limited | Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene |
CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
WO2015155739A1 (en) * | 2014-04-11 | 2015-10-15 | Scinopharm Taiwan, Ltd. | Process for the preparation of beta-c-arylglucosides |
CN105037455A (en) * | 2015-08-06 | 2015-11-11 | 天津市益科司德科技有限公司 | Synthesizing method of n-alkyl-beta-D-glucopyranoside |
-
2015
- 2015-11-16 CN CN201510786909.9A patent/CN105294624B/en active Active
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011048112A1 (en) * | 2009-10-20 | 2011-04-28 | Novartis Ag | Glycoside derivatives and uses thereof |
WO2012140597A1 (en) * | 2011-04-14 | 2012-10-18 | Novartis Ag | Glycoside derivatives and their uses for the treatment of diabetes |
WO2013068850A2 (en) * | 2011-11-07 | 2013-05-16 | Scinopharm Taiwan, Ltd. | PROCESS FOR THE PREPARATION OF β-C-ARYL GLUCOSIDES |
CN103570510A (en) * | 2012-07-19 | 2014-02-12 | 苏州中科天马肽工程中心有限公司 | One-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane |
CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
WO2015040571A1 (en) * | 2013-09-23 | 2015-03-26 | Ranbaxy Laboratories Limited | Process for the preparation of dapagliflozin |
WO2015044849A1 (en) * | 2013-09-27 | 2015-04-02 | Ranbaxy Laboratories Limited | Process for the purification of dapagliflozin |
WO2015063726A1 (en) * | 2013-10-31 | 2015-05-07 | Ranbaxy Laboratories Limited | Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene |
WO2015155739A1 (en) * | 2014-04-11 | 2015-10-15 | Scinopharm Taiwan, Ltd. | Process for the preparation of beta-c-arylglucosides |
CN104086379A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Method for synthesizing forxiga intermediate |
CN104478839A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Synthesis method of dapagliflozin |
CN104496952A (en) * | 2014-11-28 | 2015-04-08 | 深圳翰宇药业股份有限公司 | Synthesis method of dapagliflozin |
CN104529970A (en) * | 2015-01-08 | 2015-04-22 | 江苏联环药业股份有限公司 | Method for preparing Dapagliflozin |
CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
CN105037455A (en) * | 2015-08-06 | 2015-11-11 | 天津市益科司德科技有限公司 | Synthesizing method of n-alkyl-beta-D-glucopyranoside |
Non-Patent Citations (9)
Title |
---|
ANDRZEJ WISNIEWSKI ET AL: "1,6-Cyclization Reactions of Selected Aldohexopyranoses via Their 1-O-Tosyl Derivatives", 《JOURNAL OF CARBOHYDRATE CHEMISTRY》 * |
SHAHEER H. KHAN ET AL: "《Modern Methods in Carbohydrate Synthesis》", 31 December 1996, HARWOOD ACADEMIC PUBLISHERS * |
TOMOYA MACHINAMI ET AL: "1-o-mesyl derivatives of D-glucopyranose and their application to a-D-glucopyranoside synthesis", 《CHEMISTRY LETTERS》 * |
佘戟: "氧化银(Ⅰ)在糖羟基上选择性对-甲基苯磺酰化中的应用", 《应用化学》 * |
张帅阳 等: "达格列净合成路线图解", 《中国医药工业杂志》 * |
张敏 等: "四氯化锡催化剂在精细有机合成中的应用研究进展", 《零陵学院学报》 * |
李雯 等: "二丁基氧化锡在糖苷类化合物脱乙酰保护基中的应用", 《化学学报》 * |
王少敏 等: "二丁基氧化锡脱脂肪族糖苷乙酰保护基的研究", 《有机化学》 * |
赵娟 等: "卤素-镁交换制备多官能团格氏试剂的研究进展", 《化学试剂》 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107304194A (en) * | 2016-04-20 | 2017-10-31 | 扬子江药业集团上海海尼药业有限公司 | The method for preparing Dapagliflozin |
CN105859672A (en) * | 2016-04-25 | 2016-08-17 | 中国药科大学 | Synthesis method of dapagliflozin |
CN108084130A (en) * | 2017-12-15 | 2018-05-29 | 东南大学 | A kind of preparation method of antidiabetic drug Dapagliflozin |
CN108530408A (en) * | 2018-04-13 | 2018-09-14 | 海门慧聚药业有限公司 | The method for preparing Dapagliflozin |
WO2021101003A1 (en) * | 2019-11-22 | 2021-05-27 | 연세대학교 산학협력단 | Method for synthesis of gliflozin by using methanesulfonylation intermediate in continuous reaction process |
KR20210063253A (en) * | 2019-11-22 | 2021-06-01 | 연세대학교 산학협력단 | Gliflozin synthesis method using methanesulfonylated intermediates in a continuous flow chemistry process |
KR102583730B1 (en) | 2019-11-22 | 2023-10-05 | 연세대학교 산학협력단 | Gliflozin synthesis method using methanesulfonylated intermediates in a continuous flow chemistry process |
Also Published As
Publication number | Publication date |
---|---|
CN105294624B (en) | 2018-01-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105294624A (en) | Preparation method for dapagliflozin | |
CN101613341B (en) | Synthetic method of key intermediate of rosuvastatin calcium side chain | |
CN112661736B (en) | Synthetic method of tylosin intermediate | |
CN104059041A (en) | Preparation method of antidiabetic dapagliflozin intermediate | |
CN101712645B (en) | Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof | |
US20160031788A1 (en) | Method of manufacturing dicarboxylic acids and derivatives from compositions comprising ketocarboxylic acids | |
CN104529970A (en) | Method for preparing Dapagliflozin | |
CN102603820A (en) | Preparation method of 4, 6-dibenzyl 2, 3-unsaturated glucoside | |
CN104045669A (en) | Separation method suitable for chemical synthesis of salidroside for industrial production | |
CN102344401B (en) | Method for preparing amorphous atorvastatin calcium | |
CN1316010A (en) | Continuous process for preparing optically pure (S)-3-hydroxy-gamma-butyrolactone | |
CN104557845B (en) | Preparation method of lubiprostone compound | |
CN103833714A (en) | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside | |
CN102286036A (en) | Synthesis method of rhodioside | |
CN111040000A (en) | Method for preparing intermediate of gliflozin hypoglycemic drug | |
CN111116530A (en) | Method for synthesizing beraprost | |
CN1267422C (en) | Preparation method of pyriproxyfen | |
CN105399735A (en) | Empagliflozin intermediate, and preparation method and application thereof | |
CN112592326B (en) | Enantioselective synthesis method of chiral (6Z,9Z) -3, 4-epoxy octadecadiene | |
CN114716331A (en) | Preparation method of dopamine hydrochloride | |
CN113620986A (en) | Method for synthesizing medicament for treating diabetes by using D-gluconic acid-delta-lactone | |
CN106699701B (en) | The preparation method of 1-O- methyl -2,3- dideoxy-L- arabinofuranose | |
CN104262301B (en) | A kind of method of synthesis S-(+)-tetrahydro 3 furanmethanol | |
CN111662260B (en) | Synthetic method of natural product saffloneoside | |
CN107176920B (en) | A kind of new technique for synthesizing of ezetimibe |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |