CN110407891A - A kind of refining methd of SGLT-2 inhibitor intermediate - Google Patents
A kind of refining methd of SGLT-2 inhibitor intermediate Download PDFInfo
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- CN110407891A CN110407891A CN201910700371.3A CN201910700371A CN110407891A CN 110407891 A CN110407891 A CN 110407891A CN 201910700371 A CN201910700371 A CN 201910700371A CN 110407891 A CN110407891 A CN 110407891A
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- organic solvent
- sglt
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
Abstract
The invention discloses a kind of refining methd of SGLT-2 inhibitor intermediate, shown in the SGLT-2 inhibitor intermediate such as formula (I), here, substituent group definition is detailed in specification in formula (I)；The refining methd includes the following steps: that SGLT-2 inhibitor intermediate is dissolved in polar organic solvent, is cooled to ultralow temperature and non-polar organic solvent is added, to obtain the SGLT-2 inhibitor intermediate of solid.The refining methd is different from conventional recrystallization technology, can refine and be not easy cured material under room temperature, provides a kind of new selection for the purification of low melting point high-viscosity material, which is suitble to industrial amplification production.
Description
Technical field
The present invention relates to, but not limited to the technical fields of pharmaceutical synthesis, in particular to SGLT-2 inhibitor intermediate
Refining methd, especially with the technology of ultralow temperature recrystallization.
Background technique
SGLT-2 inhibitor full name is -2 inhibitor of sodium glucose cotransporter, by inhibiting SGLT-2 function direct
Reduce the raised renal glucose threshold of pathologic, reduce renal tubule glucose reabsorption ability, thus increase glucose in urine secretion and it is hypoglycemic.Its
Mainly pass through urine glucose drains (therapeutic glucose in urine) excessively come what is reached to blood sugar reducing function.It is of particular importance that the effect
Obviously weaken when blood glucose level is lower, this is greatly lowered risk of hypoglycemia.SGLT-2 inhibitor is drop novel at present
Sugared medicine, with the unique hypoglycemic approach independent of insulin secretion, existing clinical studies show, SGLT-2 inhibitor
No matter single medicine or drug combination, all have very conclusive, effective blood sugar decreasing effect.At present there are mainly three types of the listings
Drug: canagliflozin, Dapagliflozin and En Gelie are net.
Since the intermediate and bulk pharmaceutical chemicals of SGLT-2 inhibitor contain glucose structure, cause intermediate material properties normal
It is sticky under temperature, it is not easy to solidify, SGLT-2 inhibitor intermediate is mostly thick grease state, and solvent residual amount is higher, metering
Inaccuracy；Impurity content is higher, can not purify, be unfavorable for Quality control of intermediates, increases the purification pressure of finished product step.
Summary of the invention
It is the general introduction to the theme being described in detail herein below.This general introduction is not the protection model in order to limit claim
It encloses.
The present inventor studies the refining methd of SGLT-2 inhibitor intermediate, it was found that a kind of SGLT-2 inhibition
The refining methd of agent intermediate, overcomes the deficiencies in the prior art.
The present invention provides a kind of ultralow temperature method for recrystallizing and refining of SGLT-2 inhibitor intermediate, this method is different from
Conventional recrystallization technology, this method, which can refine, is not easy cured material under room temperature, provides for the purification of low melting point high-viscosity material
A kind of new selection, and this method is suitble to industrial amplification production.
Specifically, the SGLT-2 inhibits the present invention provides a kind of refining methd of SGLT-2 inhibitor intermediate
Shown in agent intermediate such as formula (I), the refining methd includes the following steps:
(1) the SGLT-2 inhibitor intermediate as shown in formula (I) is mixed with polar organic solvent, and stirring is obtained to dissolving
Solution；
(2) solution that step (1) obtains is cooled to ultralow temperature under stiring；After solid is precipitated, continue stirring to analysis
A large amount of solids out；
(3) non-polar organic solvent is added, with cured article；
(4) it filters, it is dry, obtain SGLT-2 inhibitor intermediate shown in the formula (I) of solid；
Here, substituent R in formula (I)1For hydrogen, hydroxyl or C1-C4 alkoxy；R2For methyl or chlorine；R3For in following radicals
One kind:
In embodiments of the invention, the refining methd of a kind of SGLT-2 inhibitor intermediate provided by the invention,
In, polar organic solvent described in step (1) is in C1-C6 alkanoic acid C1-C4 ester, C1-C6 alkanol, halogenated C1-C4 alkane
It is one or more of；The C1-C6 alkanoic acid C1-C4 ester can be such as Ethyl formate or ethyl acetate；The C1-C6 alkanol
It can be such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol or n-butanol；The halogenated C1-C4 alkane can be such as dichloro
Methane, chloroform, tetrachloromethane etc.；Preferably, the polar organic solvent is C1-C6 alkanoic acid C1-C4 ester, it is highly preferred that
For ethyl acetate.
In embodiments of the invention, the refining methd of a kind of SGLT-2 inhibitor intermediate provided by the invention,
In, the temperature of ultralow temperature described in the step (2) is -20 DEG C~-100 DEG C；Preferably, the temperature of the ultralow temperature be-
40 DEG C~-80 DEG C.
In embodiments of the invention, the refining methd of a kind of SGLT-2 inhibitor intermediate provided by the invention,
In, non-polar organic solvent described in the step (3) is ether organic solvent, low molecule alkanes organic solvent, aromatic hydrocarbon
One or more of class organic solvent；The ether organic solvent can be such as ether or methyl tertiary butyl ether(MTBE)；It is described
Low molecule alkanes organic solvent can be such as n-hexane or normal heptane；The arene organic solvent can be example
Such as benzene；Preferably, the non-polar organic solvent be ether organic solvent or low molecule alkanes organic solvent, it is highly preferred that
For n-hexane or normal heptane.
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein formula
(I) substituent R in1For hydrogen, hydroxyl or methoxyl group；R2For methyl or chlorine；R3For one of following radicals:
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein formula
(I) substituent R in1For hydrogen, hydroxyl or methoxyl group；R2For chlorine；R3Are as follows:
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein formula
(I) substituent R in1For hydrogen, hydroxyl or methoxyl group；R2For methyl；R3Are as follows:
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein formula
(I) substituent R in1For hydrogen, hydroxyl or methoxyl group；R2For chlorine；R3Are as follows:
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein institute
The w/v for stating step (1) SGLT-2 inhibitor intermediate as shown in formula (I) and polar organic solvent is 1:0.5~1:
5 (unit g:ml).
In some embodiments, a kind of refining methd of SGLT-2 inhibitor intermediate provided by the invention, wherein institute
The addition volume for stating step (3) non-polar organic solvent is 1~20 times of volume of step (1) described polar organic solvent.
Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification
It obtains it is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by specification and power
Specifically noted structure is achieved and obtained in sharp claim.
Specific embodiment
It, hereinafter will be to the embodiment of the present invention for the purposes, technical schemes and advantages of the application are more clearly understood
It is described in detail.It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can
With mutual any combination.
Embodiment 1:(2S, 3R, 4S, 5R, 6R) -2- (the chloro- 3- of 4- (4- (((S)-tetrahydrofuran -3- base) oxygen) benzyl) benzene
Base) -6- (methylol) tetrahydro -2H- pyrans -2,3,4,5- tetrol
100mL tetrahydrofuran, 50.0g (S) -3- (4- (the iodo- 2- chlorobenzyl of 5-) phenoxy group) four are added into 1L reaction flask
Hydrogen furans and 73.6g 2,3,4,6- tetra--O- trimethyl silicon substrate-D-Glucose acid lactone open stirring, under nitrogen protection, cold
But -30 DEG C~-20 DEG C are cooled to, 120mL isopropylmagnesium chloride-lithium chloride 1.3mol/L tetrahydrofuran solution, control temperature is added dropwise
- 30 DEG C~-20 DEG C of degree after insulation reaction 1h, is added dropwise 150mL10% monohydrate potassium aqueous solution, stirs 30min, stands point
Layer, liquid separation collect organic phase, light yellow oil, purity 88.7% are concentrated under reduced pressure to obtain.
50mL ethyl acetate is added into concentrate, opens stirring, is cooled to -55 DEG C~-65 DEG C, it is solid that a large amount of whites are precipitated
After body, 0.5h is stirred, 250mL normal heptane is added dropwise into reaction, stirs 0.5h, is filtered, filter cake is in 40 DEG C of hot air circulation drying ovens
Middle dry 15h obtains title compound 46.3g, molar yield 82.2%, purity 94.0%.
(Ultimate XB-C18,4.6 × 250mm, 5 μm or performance phase are recommended to use with octadecylsilane chemically bonded silica
When chromatographic column) be filler, using 0.005% trifluoroacetic acid aqueous solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below into
Row gradient elution；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 40 | 75 | 25 |
| 45 | 70 | 30 |
| 60 | 70 | 30 |
| 75 | 20 | 80 |
| 85 | 20 | 80 |
| 90 | 10 | 90 |
| 100 | 10 | 90 |
| 100.1 | 75 | 25 |
| 110 | 75 | 25 |
Embodiment 2:(2S, 3R, 4S, 5R, 6R) -2- (the chloro- 3- of 4- (4- (((S)-tetrahydrofuran -3- base) oxygen) benzyl) benzene
Base) -6- (methylol) 2- methoxyl group tetrahydro -2H- pyrans -3,4,5- triol
100mL methanol, 50g (2S, 3R, 4S, 5R, 6R) -2- (the chloro- 3- of 4- (4- (((S)-are added into 500mL reaction flask
Tetrahydrofuran -3- base) oxygen) benzyl) phenyl) -6- (methylol) tetrahydro -2H- pyrans -2,3,4,5- tetrols add after mixing evenly
Enter 1mL concentrated hydrochloric acid, after 20~30 DEG C of stirring 1h, reaction solution is added dropwise in 100mL saturated sodium bicarbonate solution, reaction solution is used
Ethyl acetate extracts 2 times, after using ethyl acetate 100mL, organic layer to merge every time, is washed, is had with 50mL saturated sodium chloride solution
Light yellow oil, purity 90.6% is concentrated under reduced pressure to obtain in machine layer.
50mL ethyl acetate is added into concentrate, stirs evenly, is cooled to -60 DEG C~-70 DEG C, it is solid that a large amount of whites are precipitated
After body, 0.5h is stirred, 250mL normal heptane is added dropwise into reaction, stirs 0.5h, is filtered, filter cake is in 40 DEG C of hot air circulation drying ovens
Middle dry 15h obtains title compound 46.6g, molar yield 90.5%, purity 93.9%.
(Ultimate XB-C18,4.6 × 250mm, 5 μm or performance phase are recommended to use with octadecylsilane chemically bonded silica
When chromatographic column) be filler, using 0.005% trifluoroacetic acid aqueous solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below into
Row gradient elution；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 40 | 75 | 25 |
| 45 | 70 | 30 |
| 60 | 70 | 30 |
| 75 | 20 | 80 |
| 85 | 20 | 80 |
| 90 | 10 | 90 |
| 100 | 10 | 90 |
| 100.1 | 75 | 25 |
| 110 | 75 | 25 |
Embodiment 3:(2S, 3R, 4S, 5R, 6R) -2- (the chloro- 3- of 4- (4- (((S)-tetrahydrofuran -3- base) oxygen) benzyl) benzene
Base) -6- (methylol) tetrahydro -2H- pyrans -3,4,5- triol
Acetonitrile is added in 1L dry reaction flask: methylene chloride (volume ratio 1: 1,200mL), stirring are cooled to 0~10
DEG C, 42g alchlor and 32.5g triethylsilane are sequentially added, 30min is stirred to react.By 50g (2S, 3R, 4S, 5R, 6R)-
2- (the chloro- 3- of 4- (4- (((S)-tetrahydrofuran -3- base) oxygen) benzyl) phenyl) -6- (methylol) 2- methoxyl group tetrahydro -2H- pyrrole
Mutter the acetonitriles of -3,4,5- triols: methylene chloride (volume ratio 1: 1,200mL) solution drops in above-mentioned reaction system, 1~2h drop
It is complete；20~30 DEG C of temperature control are stirred to react 1~2h.400mL water is added, removes organic solvent, the reaction solution second of 200mL × 2 under reduced pressure
Acetoacetic ester extraction, merges organic phase, after saturated salt solution washed once, light yellow oil, purity 90.5% is concentrated under reduced pressure to obtain.
50mL ethyl acetate is added into concentrate, opens stirring, is cooled to -40 DEG C~-50 DEG C, it is solid that a large amount of whites are precipitated
After body, 0.5h is stirred, 250mL normal heptane is added dropwise into reaction, stirs 0.5h, is filtered, filter cake is placed in hot air circulation drying oven
Dry 15h, obtains title compound 38.7g, molar yield 82.5%, purity 98.3%.
It is (comparable using Ultimate XB-C18,4.6 × 250mm, 5 μm or performance with octadecylsilane chemically bonded silica
Chromatographic column) it is filler, using 0.005% trifluoroacetic acid aqueous solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below carries out ladder
Degree elution；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 40 | 75 | 25 |
| 45 | 70 | 30 |
| 60 | 70 | 30 |
| 75 | 20 | 80 |
| 85 | 20 | 80 |
| 90 | 10 | 90 |
| 100 | 10 | 90 |
| 100.1 | 75 | 25 |
| 110 | 75 | 25 |
The chloro- 5- of embodiment 4:2- (1- methoxy-D-glucopyranos -1- base) -4'- ethoxy diphenyl methane
Into 1L reaction flask be added 100mL tetrahydrofuran, be added the chloro- 2- of 50g 1- (4- ethoxybenzyl) -4- iodobenzene and
2,3,4,6- tetra--O- trimethyl silicon substrate of 81.4g-D-Glucose acid lactone opens stirring, under nitrogen protection, cools
To -30 DEG C~-20 DEG C, 134mL isopropylmagnesium chloride-lithium chloride 1.3mol/L tetrahydrofuran solution is added dropwise, controls -30 DEG C of temperature
~-20 DEG C, after insulation reaction 1h, -10 DEG C are warming up to, the methanol solution 200mL of 15mL methanesulfonic acid, after being added dropwise, 20 is added dropwise
DEG C~30 DEG C under the conditions of react 2 hours.Saturation NaHCO is added dropwise3Organic solvent is concentrated under reduced pressure in quenching reaction, adjusting pH to neutrality,
The extraction of 100mL normal heptane is added, separates water layer, aqueous layer with ethyl acetate extracts 2 times, uses ethyl acetate 100mL every time, is associated with
After saturated salt solution washed once, light yellow oil product, purity 82.8% is concentrated under reduced pressure to obtain in machine phase.
50mL ethyl acetate is added into concentrate, opens stirring, is cooled to -55 DEG C~-65 DEG C, it is solid that a large amount of whites are precipitated
After body, 0.5h is stirred, 250mL normal heptane is added dropwise into reaction, stirs 0.5h, is filtered, filter cake is placed in hot air circulation drying oven
Dry 15h, obtains title compound 48.2g, molar yield 81.8%, purity 89.6%.
It is (comparable using Ultimate XB-C18,4.6 × 250mm, 5 μm or performance with octadecylsilane chemically bonded silica
Chromatographic column) it is filler, using 0.005% trifluoroacetic acid aqueous solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below carries out ladder
Degree elution；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 40 | 75 | 25 |
| 45 | 70 | 30 |
| 60 | 70 | 30 |
| 75 | 20 | 80 |
| 85 | 20 | 80 |
| 90 | 10 | 90 |
| 100 | 10 | 90 |
| 100.1 | 75 | 25 |
| 110 | 75 | 25 |
Although embodiment disclosed by the application is as above, the content only for ease of understanding the application and use
Embodiment is not limited to the application.Technical staff in any the application fields, is taken off not departing from the application
Under the premise of the spirit and scope of dew, any modification and variation, but the application can be carried out in the form and details of implementation
Scope of patent protection, still should be subject to the scope of the claims as defined in the appended claims.
Claims (10)
1. a kind of refining methd of SGLT-2 inhibitor intermediate, described shown in the SGLT-2 inhibitor intermediate such as formula (I)
Refining methd includes the following steps:
(1) the SGLT-2 inhibitor intermediate as shown in formula (I) is mixed with polar organic solvent, and stirring obtains solution to dissolving；
(2) solution that step (1) obtains is cooled to ultralow temperature under stiring；After solid is precipitated, it is big to being precipitated to continue stirring
Measure solid；
(3) non-polar organic solvent is added, with cured article；
(4) it filters, it is dry, obtain SGLT-2 inhibitor intermediate shown in the formula (I) of solid；
Here, substituent R in formula (I)1For hydrogen, hydroxyl or C1-C4 alkoxy；R2For methyl or chlorine；R3For one in following radicals
Kind:
2. refining methd according to claim 1, wherein polar organic solvent described in step (1) is selected from C1-C6 alkanoic acid
One or more of C1-C4 ester, C1-C6 alkanol, halogenated C1-C4 alkane；The C1-C6 alkanoic acid C1-C4 ester is formic acid second
Ester or ethyl acetate；The C1-C6 alkanol is methanol, ethyl alcohol, normal propyl alcohol, isopropanol or n-butanol；The halogenated C1-C4 alkane
Hydrocarbon is methylene chloride, chloroform, tetrachloromethane；Preferably, the polar organic solvent is C1-C6 alkanoic acid C1-C4 ester, more excellent
Selection of land is ethyl acetate.
3. refining methd according to claim 1, wherein non-polar organic solvent described in the step (3) is ethers
One or more of organic solvent, low molecule alkanes organic solvent, arene organic solvent；The ether organic solvent
For ether or methyl tertiary butyl ether(MTBE)；The low molecule alkanes organic solvent is n-hexane or normal heptane；The arene
Organic solvent is benzene；Preferably, the non-polar organic solvent be ether organic solvent or low molecule alkanes organic solvent, more
It preferably, is n-hexane or normal heptane.
4. refining methd according to claim 1, wherein the temperature of ultralow temperature described in the step (2) is -20 DEG C
~-100 DEG C；Preferably, the temperature of the ultralow temperature is -40 DEG C~-80 DEG C.
5. refining methd according to any one of claim 1 to 4, wherein substituent R in formula (I)1For hydrogen, hydroxyl or first
Oxygroup；R2For methyl or chlorine；R3For one of following radicals:
6. refining methd according to any one of claim 1 to 4, wherein substituent R in formula (I)1For hydrogen, hydroxyl or first
Oxygroup；R2For chlorine；R3Are as follows:
7. refining methd according to any one of claim 1 to 4, wherein substituent R in formula (I)1For hydrogen, hydroxyl or first
Oxygroup；R2For methyl；R3Are as follows:
8. refining methd according to any one of claim 1 to 4, wherein substituent R in formula (I)1For hydrogen, hydroxyl or first
Oxygroup；R2For chlorine；R3Are as follows:
9. refining methd according to any one of claim 1 to 4, wherein the step (1) is as shown in formula (I)
The w/v of SGLT-2 inhibitor intermediate and polar organic solvent is 1:0.5~1:5, unit g:ml.
10. refining methd according to any one of claim 1 to 4, wherein step (3) non-polar organic solvent
Addition volume be 1~20 times of volume of step (1) described polar organic solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111748004A (en) * | 2020-06-30 | 2020-10-09 | 药璞(上海)医药科技有限公司 | Crystal form of high-purity dapagliflozin intermediate and preparation method thereof |
| EP4023644A1 (en) * | 2020-12-30 | 2022-07-06 | Zaklady Farmaceutyczne Polpharma SA | Process for the preparation of a pharmaceutical agent |
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| CN103694230A (en) * | 2013-12-06 | 2014-04-02 | 江苏奥赛康药业股份有限公司 | High-purity canagliflozin compound and preparation method thereof |
| CN104496952A (en) * | 2014-11-28 | 2015-04-08 | 深圳翰宇药业股份有限公司 | Synthesis method of dapagliflozin |
| WO2017046655A1 (en) * | 2015-09-16 | 2017-03-23 | Optimus Drugs (P) Ltd | A novel process for the preparation of canagliflozin |
| CN106810582A (en) * | 2015-11-27 | 2017-06-09 | 广东东阳光药业有限公司 | The compound of glucopyranosyl derivatives, preparation method and application |
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| CN103694230A (en) * | 2013-12-06 | 2014-04-02 | 江苏奥赛康药业股份有限公司 | High-purity canagliflozin compound and preparation method thereof |
| CN104496952A (en) * | 2014-11-28 | 2015-04-08 | 深圳翰宇药业股份有限公司 | Synthesis method of dapagliflozin |
| WO2017046655A1 (en) * | 2015-09-16 | 2017-03-23 | Optimus Drugs (P) Ltd | A novel process for the preparation of canagliflozin |
| CN106810582A (en) * | 2015-11-27 | 2017-06-09 | 广东东阳光药业有限公司 | The compound of glucopyranosyl derivatives, preparation method and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111748004A (en) * | 2020-06-30 | 2020-10-09 | 药璞(上海)医药科技有限公司 | Crystal form of high-purity dapagliflozin intermediate and preparation method thereof |
| EP4023644A1 (en) * | 2020-12-30 | 2022-07-06 | Zaklady Farmaceutyczne Polpharma SA | Process for the preparation of a pharmaceutical agent |
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Application publication date: 20191105 |