CN104250272B - A method of it is prepared using microreactor and arranges net class pharmaceutical intermediate - Google Patents
A method of it is prepared using microreactor and arranges net class pharmaceutical intermediate Download PDFInfo
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- CN104250272B CN104250272B CN201310264507.3A CN201310264507A CN104250272B CN 104250272 B CN104250272 B CN 104250272B CN 201310264507 A CN201310264507 A CN 201310264507A CN 104250272 B CN104250272 B CN 104250272B
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- 0 CC(OC[C@]([C@@](*)[C@](C1)OC(C)=O)OC1=O)=O Chemical compound CC(OC[C@]([C@@](*)[C@](C1)OC(C)=O)OC1=O)=O 0.000 description 1
- OZNLYXKOYORFRP-UHFFFAOYSA-N CCCC(CC)F Chemical compound CCCC(CC)F OZNLYXKOYORFRP-UHFFFAOYSA-N 0.000 description 1
- GWHJZXXIDMPWGX-UHFFFAOYSA-N Cc1ccc(C)c(C)c1 Chemical compound Cc1ccc(C)c(C)c1 GWHJZXXIDMPWGX-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of methods for being prepared using microreactor and arranging net class pharmaceutical intermediate, the compound III for being dissolved in organic solvent is mixed by material channel in microreactor unit (L) respectively with organometallic reagent, and microreactor unit (H) is flowed to through (L)；The compound II of organic solvent is dissolved in mix in the microreactor unit (H) that preset temperature is (T2) with above-mentioned mixed liquor by material channel, and pass through the microreactor unit (H), it waits for flowing out from outlet after completion of the reaction, the reaction solution of the outflow is post-processed and arranges net class pharmaceutical intermediate I to get target compound.The present invention utilizes microreactor synthetic intermediate (I), the heat transfer problem of such reaction can effectively be solved, since the mixing of reactant in microreactor is extremely abundant, so as to shorten reaction time, improve reaction efficiency, microreactor has higher security performance almost without enlarge-effect, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of methods for being prepared using microreactor and arranging net class pharmaceutical intermediate, and in particular to a kind of utilization
Microreactor as shown in Figure 1 prepares anti-type-2 diabetes mellitus new drug -- Dapagliflozin (Dapagliflozin), canagliflozin
(Canagliflozin) and (1S) -1,5- dehydrations -1-C- [the chloro- 3- of 4- [[4- [[(3S)-tetrahydrochysene -3- furyls] oxygroup] benzene
Base] methyl] phenyl] and the net class pharmaceutical intermediate I of row such as-D-Glucose alcohol (Empagliflozin) method.
Background technology
Sodium glucose co-transporter 2 white 2 (SGLT2) is the treating diabetes novel targets found recently.SGLT2 inhibitor
With being conducive to the Regulation of blood glucose of 2- diabetes mellitus types, and provide and a kind of improving glycosuria by draining excessive glucose
The new mechanism of disease and its complication.Currently, many pharmaceuticals in the whole world and research and development institution are continuing to increase input, active development
Novel drugs of the SGLT2 inhibitor as treatment 2- patients with type Ⅰ DM.The Da Gelie that Bristol Myers Squibb and A Zilikang are developed jointly
Only (Dapagliflozin), the canagliflozin (Canagliflozin) of Johson ＆ Johnson's exploitation and Bo Lingeyinggehan companies open
The Empagliflozin of hair, these are all the new drugs for the treatment type-2 diabetes mellitus being had an optimistic view of extensively by market.Their structural formula point
It is not as follows：
Following intermediate compound I is undergone in the synthesis of such drug mostly：
The intermediate compound I is usually by the D-Glucose lactone of hydroxyl protection and halogenated aryl hydrocarbon in lithium reagent or grignard reagent
In the presence of carry out addition reaction and be prepared.But such exothermic heat of reaction is violent, and operation is difficult to control, industrial amplification process
Cryo Equipment requires harsh.Due to being influenced by local heating, often industry amplification is unable to get yield identical with lab scale
And product quality.
Microreactor (micro reactor) is also referred to as micro passage reaction (micro-channel reactor), is
The common name of the microchannels chemical industry equipments such as microreactor, micro-mixer, micro- heat exchanger, microcontroller.It is anti-relative to traditional batch
Answer technique, microreactor have mixed at high speed, efficient heat transfer, narrow residence time destribution, reproducible, system response is rapid,
Convenient for automation control, almost without the advantages such as enlarge-effect and high security performance.
Invention content
Technical problem to be solved by the present invention lies in provide a kind of prepare using microreactor to arrange net class pharmaceutical intermediate I
Method, to overcome various defects present in existing preparation method.
The reaction equation of the present invention is as follows：
Wherein G is to protect protecting group acetyl group or the silicon-based protecting group of C3-C9, such as trimethyl silicon substrate, benzyl etc..G ' be hydrogen,
Acetyl group, benzyl etc., in same compound.X is halogen, representative example such as bromine or iodine.Aryl or the substitution that Ar is C6-C15
Aryl, such as phenyl, to ethoxyl phenenyl, 5- p-fluorophenyl -2- thienyls, 4- ((S)-tetrahydrofuran -3- oxygroups) phenyl.R
For substituent group, such as chlorine, methyl or hydrogen.M is methyl or hydrogen.
Microreactor of the present invention, structure is as shown in Figure 1, micro- including at least 3 material channels A, B, C and 2
Reaction member L, H and one outlet D.Wherein, together with micro- reaction member L and H mounted on top, micro- reaction member L is located at H
Surface；Material channel A, B are respectively arranged on the same side of micro- reaction member L, and material channel C is set to the one of micro- reaction member H
Side, and be in relative position with material channel A, B；Export the other side that D is set to micro- reaction member H.
Further respectively had in micro- reaction member L and H material channel (material channel can be zigzag, linear type,
Helical form or bending etc. all can), the two is connected by a vertical material.Wherein, the material in micro- reaction member L
Passage end is connected with material channel A, B, and the other end is connected with towards the vertical material channel in micro- reaction member H；Institute
State material channel one end in micro- reaction member H with from micro- reaction member L vertical material channel and material channel C be connected
It connects, the other end is connected with outlet D, to make entire microreactor form access.
It is of the present invention that the method for arranging net class pharmaceutical intermediate I is prepared using microreactor, include the following steps：
(1) the compound III for being dissolved in organic solvent is flowed by material channel A, B respectively with organometallic reagent default
Temperature is mixing in the microreactor unit L of T1, and flows to microreactor unit H through L；
(2) the compound II for being dissolved in organic solvent is mixed by material channel C and above-mentioned mixed liquor in micro- reaction member H
Close, and by micro- reaction member H that preset temperature is T2, wait for after completion of the reaction from outlet D outflows, to the reaction solution of the outflow into
Row post-processing is to get target compound -- arrange net class pharmaceutical intermediate I.
In the above method, the compound III solution concentrations described in step (1) are 0.01g/mL~2g/mL, compound III
Flow velocity with organometallic reagent is respectively 0.1mL/min~5.0mL/min.
The organometallic reagent is selected from：The organolithium reagent of C4 or more, such as n-BuLi, s-butyl lithium or tert-butyl lithium
Reagent；Or the chain alkane grignard reagent of C1-C4 and the mixed solution of lithium chloride, as ethyl grignard reagent or isopropyl format try
The molar ratio of the mixed solution of agent and lithium chloride, the two is 1: 0.9~1: 1.2.
The preset temperature T1 of micro- reaction member L is -90~20 DEG C, preferably -80~-5 DEG C.
In the above method, the compound II solution concentrations described in step (2) are 0.01g/mL~2g/mL, compound II's
Flow velocity is 0.1mL/min~5.0mL/min.
The preset temperature T2 of micro- reaction member H is -90~20 DEG C, preferably -80~-15 DEG C.
In the above method, the organic solvent is selected from：The ethers organic solution of C2-C7, such as ether, methyl phenyl ethers anisole；Or
Tetrahydrofuran, 2- methyltetrahydrofurans；Or the arene solution of C6-C9, such as benzene,toluene,xylene, trimethylbenzene.
After completion of the reaction, the reaction solution flowed out from outlet D is collected in acidic aqueous solution (such as formic acid, acetic acid, propionic acid)
In, or be collected in the methanol solution containing methanesulfonic acid, the post-processing such as agitated, extraction, washing, salt are washed, dry concentration to get
Target compound -- arrange net class pharmaceutical intermediate I.
The present invention goes out target compound using microreactor success Fast back-projection algorithm -- arrange net class pharmaceutical intermediate I, Ke Yiyou
Effect solves the heat transfer problem of such reaction, and since the mixing of reactant in microreactor is extremely abundant, so as to shorten reaction
Time improves reaction efficiency, and microreactor has higher security performance almost without enlarge-effect, is suitble to industry
Metaplasia is produced.
Description of the drawings
Fig. 1 is the structural schematic diagram of the microreactor of the present invention, and wherein A, B, C is respectively material channel, and L, H are respectively micro-
Reactor unit, D are outlet, and T1, T2 are respectively the preset temperature of microreactor unit L, H.
Specific implementation mode
Technical scheme of the present invention is described in further detail below in conjunction with specific embodiment, but the embodiment does not limit this
The protection domain of invention.It should be noted that following embodiment is merely illustrative of the technical solution of the present invention and unrestricted, although
It is described the invention in detail with reference to preferred embodiment, it will be understood by those of ordinary skill in the art that, it can be to invention
Technical solution be modified or replaced equivalently, without departing from the spirit of the technical scheme of the invention and range, should all cover
In scope of the presently claimed invention.
Example 1 Dapagliflozin intermediate compound I a-- (3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- ethoxy benzyls) phenyl) -6-
(methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4, the synthesis of 5- triols.
Method 1
The diethyl ether solution 163mL (163g, 0.5mol) for preparing the bromo- 1- of 4- chloro- 2- (4- ethoxybenzyls) benzene of 1g/mL, to
The above diethyl ether solution, coutroi velocity 0.1mL/min are passed through in material channel A.2.5M is being passed through into material channel B just simultaneously
Butyl lithium solution total 200mL, coutroi velocity 0.12mL/min, wherein the preset temperature T1 of micro- reaction member L is -80~-75
℃.Then to (3R, 4S, 5R, the 6R) -3 for being passed through 0.5g/mL in material channel C, 4,5- tri- (trimethylsiloxy group) -6- ((three
Methyl siloxy) methyl) tetrahydrochysene -2H- pyran-2-ones diethyl ether solution 514mL (257g, 0.55mol), coutroi velocity is
0.3mL/min, wherein the preset temperature T2 of micro- reaction member H is -80~-70 DEG C.It waits for after completion of the reaction, D outflows being exported
Reaction solution is passed through in the methanol solution containing 0.6N methanesulfonic acids (1L), is controlled 15~25 DEG C of temperature, is finished when system is all passed through
Afterwards, 16h is stirred, system is quenched by saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, saturated common salt water washing, anhydrous sulphur
Sour sodium drying, is concentrated to give target product to get Dapagliflozin intermediate compound I a-- (3R, 4S, 5S, 6R) -2- (4- chloro- 3- (4- ethoxies
Base benzyl) phenyl) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols, 180g, yield 82%.
HPLC ES/MS m/z：461((M+Na)+)
Method 2
Prepare 0.2g/mL the bromo- 1- of 4- chloro- 2- (4- ethoxybenzyls) benzene tetrahydrofuran solution 815mL (163g,
0.5mol), the above tetrahydrofuran solution, coutroi velocity 1mL/min are passed through into material channel A.Lead to simultaneously into material channel B
Enter n-butyllithium solution total 200mL, the coutroi velocity 0.25mL/min of 2.5M, wherein the preset temperature T1 of micro- reaction member L be-
80~-75 DEG C.Then to (3R, 4S, 5R, the 6R) -3 for being passed through 0.4g/mL in material channel C, 4,5- tri- (trimethylsiloxy groups) -
The tetrahydrofuran solution 643mL (257g, 0.55mol) of 6- ((trimethylsiloxy group) methyl) tetrahydrochysene -2H- pyran-2-ones, control
Flow velocity is 0.8mL/min, wherein the preset temperature T2 of micro- reaction member H is -80~-70 DEG C.It waits for after completion of the reaction, D being exported
The reaction solution of outflow is passed through in the methanol solution containing 0.6N methanesulfonic acids (1L), 15-25 DEG C of temperature is controlled, when system is all passed through
After, 16h is stirred, system is quenched by saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, saturated common salt water washing, nothing
Aqueous sodium persulfate is dried, and target product, i.e. Dapagliflozin intermediate compound I a-- (3R, 4S, 5S, 6R) -2- (4- chloro- 3- (4- second are concentrated to give
Oxy-benzyl) phenyl) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols, 193g, yield 88%.
HPLC ES/MS m/z：461((M+Na)+)
Example 2 canagliflozin intermediate compound I b-- (3R, 4S, 5R, 6R) -6- (acetonyl) -2- (3- ((5- (4- fluorophenyls)
Thiophene -2- bases) methyl) -4- aminomethyl phenyls) -2- tetrahydrochysene -2H- pyrans -3,4, the synthesis of 5- triacetates.
Prepare the toluene solution 2040mL of 2- (2- methyl -5- iodine benzyl) -5- (4- fluorophenyls) thiophene of 0.1g/mL
(204g, 0.5mol) is passed through the above toluene solution, coutroi velocity 2mL/min into material channel A.Simultaneously into material channel B
It is passed through the isopropyl grignard reagent of 2M and solution (grignard reagent is 1: 1 with lithium chloride molar ratio) total 250mL of lithium chloride, control
Flow velocity is 0.23mL/min, wherein the preset temperature T1 of micro- reaction member L is -10~0 DEG C.Then to being passed through in material channel C
(2R, 3R, 4S, 5R) -2- (acetyl-o-methyl) -6- carbonyl tetrahydrochysene -2H- pyrans -3,4 of 0.2g/mL, the tetrahydrochysene of 5- triacetates
Tetrahydrofuran solution 952mL (190g, 0.55mol), coutroi velocity 0.9mL/min, wherein the preset temperature T2 of micro- reaction member H
It is -35~-15 DEG C.It waits for after completion of the reaction, the reaction solution for exporting the outflow of the places D is passed through mixing containing 38mL acetic acid and 425mL water
It closes in liquid, controls 15~25 DEG C of temperature, after system is all passed through, stir 15min, system passes through saturated sodium bicarbonate water
Solution is quenched, ethyl acetate extraction, saturated common salt water washing, and anhydrous sodium sulfate drying concentrates to get target compound Kan Gelie
Net intermediate compound I b-- (3R, 4S, 5R, 6R) -6- (acetonyl) -2- (3- ((5- (4- fluorophenyls) thiophene -2- bases) methyl) -4-
Aminomethyl phenyl) -2- tetrahydrochysene -2H- pyrans -3,4,5- triacetates, 260g, yield 83%.
HPLC ES/MS m/z：651((M+Na)+)
Example 3 canagliflozin intermediate compound I c-- (3R, 4S, 5R, 6R) -3,4,5- tri- (benzyloxy) -6- (benzyloxymethyl) -2-
The synthesis of (3- ((5- (4- fluorophenyls) thiophene -2- bases) methyl) -4- aminomethyl phenyls) tetrahydrochysene -2H- pyrans -2- oxygen alkane.
Prepare the toluene solution 2040mL of 2- (2- methyl -5- iodine benzyl) -5- (4- fluorophenyls) thiophene of 0.1g/mL
(204g, 0.5mol) is passed through the above toluene solution, control speed 2mL/min into material channel A.It is passed through simultaneously into channel B
Ethyl grignard reagent and lithium chloride solution (grignard reagent is 1: 1.2 with lithium chloride molar ratio) total 250mL of 2M, coutroi velocity
0.23mL/min, wherein the preset temperature T1 of micro- reaction member L is -10~0 DEG C.Then to being passed through 0.2g/mL in material channel C
(3R, 4S, 5R, 6R) -3, the tetrahydrofuran solution of 4,5- tri- (benzyloxy) -6- (benzyloxymethyl) tetrahydrochysene -2H- pyran-2-ones
1480mL (296g, 0.55mol), coutroi velocity 1.4mL/min, wherein the preset temperature T2 of micro- reaction member H be -35~-
15℃.It waits for after completion of the reaction, the reaction solution for exporting D outflows being passed through in the mixed liquor containing 38mL acetic acid and 425mL water, is controlled
15-25 DEG C of temperature stirs 15min after system is all passed through, and system is quenched by saturated sodium bicarbonate aqueous solution, second
Acetoacetic ester extracts, saturated common salt water washing, and anhydrous sodium sulfate drying concentrates to get target compound canagliflozin intermediate
Ic-- (3R, 4S, 5R, 6R) -3,4,5- tri- (benzyloxy) -6- (benzyloxymethyl) -2- (3- ((5- (4- fluorophenyls) thiophene -2- bases)
Methyl) -4- aminomethyl phenyls) tetrahydrochysene -2H- pyrans -2- oxygen alkane, 324g, yield 79%.
HPLC ES/MS m/z：843((M+Na)+)
Example 4Empagliflozin intermediate compound Is d-- (3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- ((S)-tetrahydrofurans -
3- oxygroups) benzyl) phenyl) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4, the synthesis of 5- triols.
Prepare the tetrahydrofuran solution 414mL of (S) -3- (4- (the chloro- 5- iodine benzyls of 2-) phenolic group) tetrahydrofuran of 0.5g/mL
(207g, 0.5mol) is passed through the tetrahydrofuran solution, coutroi velocity 0.5mL/min into material channel A.Simultaneously to material
The solution (grignard reagent is 1: 0.9 with lithium chloride molar ratio) of isopropyl grignard reagent and lithium chloride that 2M is passed through in the B of channel is altogether
250mL, coutroi velocity 0.30mL/min, wherein the preset temperature T1 of micro- reaction member L is -15~-10 DEG C.Then to material
It is passed through in channel C (3R, 4S, 5R, the 6R) -3 of 0.3g/mL, 4,5- tri- (trimethylsiloxy group) -6- ((trimethylsiloxy group) first
Base) tetrahydrochysene -2H- pyran-2-ones tetrahydrofuran solution 857mL (257g, 0.55mol), coutroi velocity 1.0mL/min,
In micro- reaction member H preset temperature T2 be -40~-20 DEG C.It waits for after completion of the reaction, the reaction solution flowed out at D being exported and be passed through
In methanol solution containing 0.6N methanesulfonic acids (1L), 15~25 DEG C of temperature is controlled, after system is all passed through, stirs 16h,
System is quenched by saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, saturated common salt water washing, and anhydrous sodium sulfate drying is dense
Contracting, obtains target compound Empagliflozin intermediate compound Is -- (3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- ((S)-tetrahydrochysene furans
Mutter -3- oxygroups) benzyl) phenyl) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols, 180g, yield
75%.
HPLC ES/MS m/z：503((M+Na)+)。
Claims (7)
1. a kind of preparing the method for arranging net class pharmaceutical intermediate I using microreactor, which is characterized in that include the following steps：
(1) the compound III of organic solvent will be dissolved in organometallic reagent respectively by the material channel of microreactor (A, B)
Mixing in the microreactor unit (L) that preset temperature is (T1) is flowed into, and microreactor unit (H), compound are flowed to through (L)
The flow velocity of III and organometallic reagent is respectively 0.1mL/min~5.0mL/min；The microreactor unit (L) is preset
Temperature (T1) is -15~20 DEG C；
Wherein, the microreactor includes at least 3 material channels (A, B, C) and 2 micro- reaction members (L) and (H), Yi Jiyi
A outlet (D)；Together, micro- reaction member (L) is located at the surface of (H) for micro- reaction member (L) and (H) mounted on top；Material
Channel (A, B) is respectively arranged on the same side of micro- reaction member (L), and material channel (C) is set to the side of micro- reaction member H, and with
Material channel (A, B) is in relative position；Export the other side that (D) is set to micro- reaction member (H)；Micro- reaction member (L) and
(H) material channel is further respectively had in, the two is connected by a vertical material channel；
(2) the compound II for being dissolved in organic solvent is interior in microreactor unit (H) by material channel (C) and above-mentioned mixed liquor
Mixing, and by the microreactor unit (H) that preset temperature is (T2), wait for flowing out from outlet (D) after completion of the reaction, to the outflow
Reaction solution post-processed to get target compound -- arrange net class pharmaceutical intermediate I；The flow velocity of compound II is 0.1mL/
Min~5.0mL/min；
Reaction equation is as follows：
Wherein G is protecting group acetyl group, trimethyl silicon substrate or benzyl；G ' is hydrogen, acetyl group or benzyl；X is bromine or iodine；Ar is
Phenyl, to ethoxyl phenenyl, 5- p-fluorophenyl -2- thienyls or 4- ((S)-tetrahydrofuran -3- oxygroups) phenyl；R is chlorine, first
Base or hydrogen；M is methyl or hydrogen.
2. according to the method described in claim 1, it is characterized in that, the compound III solution concentrations described in step (1) are
0.01g/mL~2g/mL.
3. according to the method described in claim 1, it is characterized in that, the organometallic reagent described in step (1) is selected from：Normal-butyl
Lithium, tert-butyl lithium；And the mixed solution of ethyl grignard reagent or isopropyl grignard reagent and lithium chloride, the molar ratio of the two are
1:0.9~1:1.2.
4. according to the method described in claim 1, it is characterized in that, the compound II solution concentrations described in step (2) are
0.01g/mL~2g/mL.
5. according to the method described in claim 1, it is characterized in that, the preset temperature (T2) of the microreactor unit (H)
It is -90~20 DEG C.
6. according to the method described in claim 1, it is characterized in that, the organic solvent is selected from：Ether, methyl phenyl ethers anisole, tetrahydrochysene
Furans, 2- methyltetrahydrofurans, benzene,toluene,xylene, or trimethylbenzene.
7. according to the method described in claim 1, it is characterized in that, the reaction solution flowed out from outlet (D) is collected in acid water
It in solution, or is collected in the methanol solution containing methanesulfonic acid, agitated, extraction, washing, salt are washed, dry, concentrated to get mesh
Mark compound -- arrange net class pharmaceutical intermediate I.
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| CN201310264507.3A CN104250272B (en) | 2013-06-27 | 2013-06-27 | A method of it is prepared using microreactor and arranges net class pharmaceutical intermediate |
| PCT/CN2014/080740 WO2014206299A1 (en) | 2013-06-27 | 2014-06-25 | Method for preparing liflozin drug intermediate using microreactor |
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| EP3256482B1 (en) * | 2015-02-09 | 2019-11-27 | Indoco Remedies Limited | Process for the preparation of sglt inhibitor compounds |
| CN105254610B (en) * | 2015-11-06 | 2018-03-09 | 西安近代化学研究所 | The method that continuous stream micro passage reaction prepares difluoro piperonal |
| CN105753835B (en) * | 2016-04-11 | 2018-06-12 | 黑龙江鑫创生物科技开发有限公司 | A kind of method for synthesizing 2- (4- fluorophenyls) thiophene |
| CN106632288B (en) * | 2016-11-07 | 2019-07-16 | 安徽九华华源药业有限公司 | En Gelie net preparation method |
| CN106866645B (en) * | 2017-02-14 | 2019-07-23 | 齐鲁天和惠世制药有限公司 | A method of Kan Gelie piperazine is prepared using microreactor one kettle way continuous flow |
| CN108276414B (en) * | 2018-01-26 | 2019-07-23 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of citric acid tropsch imatinib |
| CN109400561B (en) * | 2018-12-21 | 2021-06-01 | 山东豪迈化工技术有限公司 | Synthetic method of dapagliflozin |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
| CN115867538A (en) | 2020-06-05 | 2023-03-28 | 新梅斯托克公司 | Preparation of highly pure amorphous dapagliflozin |
| CN113549042B (en) * | 2021-07-23 | 2022-09-27 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
| CN114394993B (en) * | 2021-11-11 | 2023-11-10 | 苏州正济药业有限公司 | Preparation method of dapagliflozin intermediate |
| CN114570303A (en) * | 2022-03-02 | 2022-06-03 | 南京市计量监督检测院 | Microchannel reactor and method for preparing dapagliflozin intermediate based on reactor |
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| US20090326215A1 (en) * | 2004-03-16 | 2009-12-31 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
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