WO2017206808A1 - Procédé de préparation de matière eutectique de la dapagliflozine - Google Patents

Procédé de préparation de matière eutectique de la dapagliflozine Download PDF

Info

Publication number
WO2017206808A1
WO2017206808A1 PCT/CN2017/086106 CN2017086106W WO2017206808A1 WO 2017206808 A1 WO2017206808 A1 WO 2017206808A1 CN 2017086106 W CN2017086106 W CN 2017086106W WO 2017206808 A1 WO2017206808 A1 WO 2017206808A1
Authority
WO
WIPO (PCT)
Prior art keywords
dapagliflozin
eutectic
zinc
chloro
preparing
Prior art date
Application number
PCT/CN2017/086106
Other languages
English (en)
Chinese (zh)
Inventor
马帅
潘竞
刘珍仁
周伟澄
Original Assignee
上海医药工业研究院
中国医药工业研究总院
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 上海医药工业研究院, 中国医药工业研究总院 filed Critical 上海医药工业研究院
Publication of WO2017206808A1 publication Critical patent/WO2017206808A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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

Definitions

  • the invention relates to the field of drug synthesis, in particular to a preparation process of a hypoglycemic drug dapagliflozin eutectic.
  • Daggliflozin (English name: Dapagliflozin) is a new Sodium glucose co-transporters 2 (SGLT-2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca. Approved by the European Commission on November 14, 2012, and marketed in the United States on January 8, 2014, to improve glycemic control in adult patients with type 2 diabetes by combining diet and exercise; the trade name is Farxiga, currently offering 5 mg and 10 mg tablets. At the same time, a combination of dapagliflozin and metformin hydrochloride has also been marketed.
  • SGLT-2 Sodium glucose co-transporters 2
  • dapagliflozin is (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H - pyran-3,4,5-triol
  • the chemical formula is C 21 H 25 ClO 6 , CAS No. 461432-26-8
  • the structural formula is shown as 2
  • the structural formula is as shown in 1.
  • the route uses 2-chloro-5-bromobenzoic acid (12) as raw material to react with phenethyl ether to form intermediate 11 and then triethylsilane to obtain intermediate 10; intermediate 10 and n-butyl
  • the lithium is reacted at -78 ° C, and then subjected to a nucleophilic addition reaction with the intermediate 9, and then methoxylated to obtain the intermediate 8; the intermediate 8 is subjected to acylation reduction and deprotection to obtain the intermediate 2.
  • the disadvantage of this method is that the ⁇ -type C-aryl glycosidic bond synthesis of the compound is carried out at a low temperature of -78 ° C, which is obviously difficult to meet the needs of industrial production; and, through nucleophilic addition, methoxylation, The five-step reaction of acetylation, reduction and hydrolysis can synthesize the ⁇ -type C-aryl glycosidic bond.
  • the procedure is relatively long, and the purity of the intermediate 2 is only 94%.
  • the intermediate 14 of the route is reacted with di-n-butyl-n-hexylmagnesium for 48 hours at 0 ° C, and then reacted with zinc bromide to prepare an organozinc reagent by Br/Mg/Zn exchange reaction, and then with intermediate 4
  • Intermediate 3 was prepared by nucleophilic substitution reaction; finally, intermediate 2 was obtained by deprotection with sodium methoxide.
  • the synthesis method is relatively novel, and the synthesis step is short. However, the research experiment is conducted only as a synthesis method, and the post treatment of the intermediate 3 is performed by column chromatography. The purity of the intermediate 2 produced was not reported.
  • the di-n-butyl-n-hexylmagnesium reagent used in the route is not a commonly used reagent, and is not commercially available in China. It can only be prepared by reacting dibutylmagnesium with n-hexyllithium reagent before the test, and the operation is cumbersome and difficult to mass. use.
  • the route uses 1,6-anhydroglucose (20) as a raw material, protects the 2,4-hydroxyl group by tert-butyldiphenylchlorosilane, and then protects the 3-position hydroxyl group with phenylmagnesium bromide.
  • Intermediate 18 The intermediate 14 is subjected to an Br/Mg/Al exchange reaction to prepare an organoaluminum reagent 16, which is reacted with an intermediate 18 to form an intermediate 15, and finally, deprotected to obtain an intermediate 2.
  • the synthesis method is very novel and is also used as a synthetic methodological study.
  • the purification of the intermediates is carried out by column chromatography.
  • the 1,6-anhydroglucose (20) used in the route is very expensive; and the multi-step reaction in the route uses a format reagent, a preparation format reagent or an organoaluminum reagent, which is cumbersome and cumbersome to perform, and is difficult to scale synthesis.
  • the purity of the intermediate 2 produced was not reported.
  • the route uses 2-chloro-5-iodobenzoic acid (24) as raw material to form intermediate 22 by Friedel acylation and reduction reaction, and exchange with I-Mg at -5 ° C with isopropyl magnesium chloride lithium chloride.
  • the intermediate 8 is obtained by nucleophilic addition and methoxylation with the intermediate 9, and then the intermediate 2 is obtained by reduction with triethylsilane, and the intermediate 2 is further purified by co-crystallizing with L-valine. Finally, The pure intermediate 2 was obtained by removing L-valine.
  • This route is a modified route of Route 1, which replaces n-butyllithium with isopropylmagnesium chloride chloride to raise the reaction temperature of the reaction from -78 °C to -5 °C.
  • Route 1 replaces n-butyllithium with isopropylmagnesium chloride chloride to raise the reaction temperature of the reaction from -78 °C to -5 °C.
  • the obtained intermediate 2 is not optically pure, and needs to be purified by co-crystallizing with L-valine, and the work amount of post-treatment is increased, and finally the purity of the intermediate 2 is 99.3%.
  • route one and route four are commonly used synthetic methods for ⁇ -type C-aryl glycosidic bonds, and the route is long, and the optical purity of the obtained product is not high, and further purification is required.
  • Post processing is cumbersome.
  • the reaction required at -78 °C in Route 1 requires high equipment and high energy consumption, which undoubtedly increases the cost.
  • Route 2 and Route 3 are new methods, most of the purification of intermediates used is column chromatography. Such a process is not suitable for scale production in factories; and some of the synthetic routes are used. Reagents are not commercially available or expensive, and there is no advantage in such route costs. Therefore, there is an urgent need to find a new method for the synthesis of dapagliflozin, and to enable industrial production, and the route has a cost advantage.
  • the price of commercially available 1.0 mol/L di-n-butyl magnesium n-heptane solution 500 mL is 1380 yuan
  • the price of 1.6 mol/L n-hexyl lithium n-hexane solution 500 mL is 950 yuan
  • 2.5 mol/L n-butyl lithium is only 145 yuan. Therefore, the method for preparing dapagliflozin by preparing an organozinc reagent by X/Li/Zn and then synthesizing the ⁇ -type C-aryl glycosidic bond designed by the invention has the advantages of cost, ease of operation and industrialization. Very obvious advantage.
  • the original compound company uses a eutectic method in the production of dapagliflozin to make dapagliflozin together with a solvent or an amino acid compound, since the compound 2 sugar ring structure contains four hydroxyl groups and is easy to absorb moisture and deteriorate.
  • the crystal is made into a relatively stable solid, easy to store, stable and controllable in quality, and easy to prepare.
  • the marketed dapagliflozin forms a stable eutectic with (S)-1,2-propanediol and water (1).
  • the original crystal form patent (CN101479287B, CN103145773B) reported that all 11 crystal forms are dapagliflozin solvate or dapagliflozin. Crystal.
  • Method 1 The preparation method is as follows:
  • Method 2 The preparation method is as follows:
  • Compound 8 is subjected to reduction of methoxy group by triethylsilane and boron trifluoride diethyl ether complex, and then the reaction solution is extracted with methyl tert-butyl ether (MTBE), and (S)-1,2-propanediol ( (S)-PG), a seed crystal of the compound 1 is added, and then cyclohexane is added to crystallize, and the mixture is separated and dried to obtain a eutectic of the compound (1) of the type Ia.
  • MTBE methyl tert-butyl ether
  • (S)-1,2-propanediol ( (S)-PG) a seed crystal of the compound 1 is added, and then cyclohexane is added to crystallize, and the mixture is separated and dried to obtain a eutectic of the compound (1) of the type Ia.
  • the above two methods for preparing the eutectic are all used in the cyclohexane solvent, which is listed in the appendix of the 2015 edition of the Pharmacopoeia (four parts) as the second type of solvent that should be restricted, with a residual limit of 0.388%.
  • the solvent residue of the final product obtained must reach the specified limit, and the post-treatment process is complicated, time-consuming and labor-intensive, and the production cost is correspondingly increased.
  • the invention finds a suitable solvent on the basis of the synthetic route to prepare a medicinal crystal form, and has obvious advantages in both the method and the process operation steps.
  • the technical problem to be solved by the present invention is to solve the problem that the prior art in the preparation of the dapagliflozin eutectic has complicated reaction steps, the synthesis process and the post-treatment are cumbersome, the reagents used are not easy to obtain, and the medicinal crystal solvent residue treatment is prepared.
  • the cumbersome problem provides a preparation process for the medicinal dapagliflozin eutectic which is more suitable for industrial production.
  • the invention uses 4-chloro-3-(4-ethoxyphenyl)methylphenyl halide (compound 6) as a raw material, and compound 6 is reacted with alkyllithium in a suitable solvent, and then reacted with zinc salt.
  • the nucleophilic substitution reaction of glucopyranose (compound 4) gives compound 3, and then the pivaloyl protecting group of compound 3 is removed to obtain dapagliflozin 2,2 with (S)-1,2-propanediol and water.
  • Glycine eutectic 1 (Compound 1).
  • the invention provides a preparation process of dapagliflozin eutectic, comprising the following steps:
  • the synthetic route is as follows:
  • the structure of the 4-chloro-3-(4-ethoxybenzyl)phenyl halide 6 is selected from the group consisting of bromine Br or iodine I.
  • the reaction solvent may be an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diglyme, diethyl ether. , isopropyl ether, n-butyl ether, methyl tert-butyl ether, cyclopentyl methyl ether; may also be an aromatic hydrocarbon solvent such as toluene, xylene, fluorobenzene, chlorobenzene; or a mixed solvent of ethers and aromatic hydrocarbons
  • the mixed solvent of n-butyl ether, cyclopentyl methyl ether and toluene is preferred. More preferably, the ratio of the ether to the aromatic hydrocarbon in the mixed solvent is from 1:1 to 1:4.
  • the preparation of the organozinc reagent bis[4-chloro-3-(4-ethoxybenzyl)phenyl]zinc is compound 6 in a suitable solvent. It is prepared by reacting with an alkyl lithium and then reacting with a zinc salt.
  • the alkyllithium reagent used for preparing the organozinc reagent may be n-butyllithium, sec-butyllithium, tert-butyllithium, n-hexyllithium, trimethylsilylmethyllithium, methyllithium or the like, preferably n-butyllithium, N-hexyllithium; the molar ratio of the alkyllithium reagent to the compound 6 is from 0.9:1 to 2:1, preferably from 1:1 to 1.2:1.
  • reaction temperature of the phenyl halide 6 with the alkyl lithium reagent is -60 ° C to 25 ° C, and the reaction time is 1 h to 10 h to prepare an organozinc reagent of the compound 6.
  • the zinc salt in the step 1), may be zinc bromide, zinc iodide, zinc triflate, preferably zinc bromide.
  • the molar ratio of the zinc salt to the compound 6 is from 0.4:1 to 3:1, preferably 0.5:1.
  • the solution for dissolving the zinc salt may be tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diglyme, diethyl ether, diisopropyl ether, n-butyl ether, methyl tert-butyl ether, cyclopentane.
  • Methyl ether preferably n-butyl ether, methyl tert-butyl ether, cyclopentyl methyl ether.
  • the addition of the corresponding lithium salt having the same negative ion as the zinc salt used can increase the solubility of the zinc salt in the solvent, and the lithium salt may be lithium bromide, lithium iodide or lithium trifluoromethanesulfonate; accordingly, lithium bromide is preferred.
  • the molar ratio of the lithium salt to the compound 6 is from 0.4:1 to 3:1, preferably 0.5:1.
  • the reaction temperature for preparing the organozinc reagent is -20 ° C to 25 ° C, and the reaction time is 0.5 h. At 10 h, an organozinc reagent of Compound 6 can be prepared.
  • the obtained organozinc reagent-bis[4-chloro-3-(4-ethoxybenzyl)phenyl]zinc and 2,3, A nucleophilic substitution reaction of 4,6-tetra-O-pivaloyl- ⁇ -D-bromoglucopyranose (compound 4), wherein 2,3,4,6-tetra-O-pivaloyl- ⁇
  • the molar ratio of the -D-bromoglucopyranose 4 to the compound 6 is from 0.8:1 to 3:1, preferably from 0.8:1 to 1.25:1.
  • the reaction temperature of the organozinc reagent-bis[4-chloro-3-(4-ethoxybenzyl)phenyl]zinc and 6 for nucleophilic substitution is controlled in the range of 25 ° C to 140 ° C, preferably 80 ° C to 120 ° C.
  • the reaction time of the organozinc reagent-bis[4-chloro-3-(4-ethoxybenzyl)phenyl]zinc and 6 for nucleophilic substitution is from 0.5 h to 24 h, preferably from 3 h to 6 h. Compound 3 can be obtained.
  • step 2) the pivaloyl protecting group of the compound 3 is removed to obtain dapagliflozin 2, and then directly co-crystallized with (S)-1,2-propanediol and water in a suitable solvent after seeding. .
  • the protecting group on the sugar ring is removed, and the organic base or inorganic base used may be sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium acetate, or hydroxide.
  • the solvent which can be used for sodium, potassium hydroxide or lithium hydroxide is methanol, ethanol, isopropanol, n-butanol, tert-butanol or water.
  • the molar ratio of the organic base to the compound 3 is from 0.5:1 to 5:1, preferably from 2:1 to 4:1.
  • the reaction temperature is controlled from 25 ° C to 100 ° C, preferably from 50 ° C to 80 ° C.
  • the reaction time is from 0.5 h to 24 h, preferably from 3 h to 5 h.
  • the solvent added to the solution after removing the protecting group on the sugar ring may be methyl tert-butyl ether, diisopropyl ether, ethyl acetate or isopropyl acetate. Preferred are methyl tert-butyl ether and isopropyl acetate.
  • the poor solvent added in the eutectic step may be cyclohexane, n-heptane, n-hexane, preferably n-heptane. More preferably, suitable solvents for the co-crystallization step are isopropyl acetate and n-heptane.
  • the present invention uses 4-chloro-3-(4-ethoxyphenyl)methylphenyl halide 6 as a raw material to prepare an organozinc reagent by X/Li/Zn (X is Br or I) exchange reaction.
  • X is Br or I
  • a direct nucleophilic substitution reaction with compound 4 can be carried out to obtain a key intermediate with a ⁇ -type chiral glycosidic bond, compound 3, and then the compound 3 is deprotected to remove the pivaloyl group to obtain dapagliflozin 2
  • the synthesis step is very short, the operation is simple, and it is more suitable for industrial production.
  • the method for preparing the organozinc reagent of Compound 6 by the X/Li/Zn exchange reaction in the present invention has not been reported.
  • the reagents used in the synthesis are conventional bulk reagents, which are cheap and easy to obtain, and the route cost is low.
  • the method of the present invention synthesizes daclixene ⁇ -type chiral glycosidic bond, and the reaction temperature only needs to be controlled at -20 ° C to complete the reaction well, avoiding the ultra-low temperature reaction of -78 ° C in the patent literature, and the requirement for equipment is low. Easy to industrialize production.
  • the product yield was 72.42%, the optical purity was as high as 100%, and the ⁇ -type diastereomer was not contained.
  • the present invention deprotects the compound 3 from the pivaloyl group, and then directly eutectic with (S)-1,2-propanediol and water in a solvent of isopropyl acetate and n-heptane to obtain a type Ia.
  • the n-heptane solvent used in the present invention is listed as a third type of solvent in the 2015 edition of the Pharmacopoeia (four parts) appendix, and the residue limit is 0.5%.
  • the post-treatment is simple, the operation is simplified, and the purity is high.
  • Figure 1 is a thermogravimetric analysis (TGA) curve of Compound 1.
  • DSC differential scanning calorimetry
  • Figure 3 is a powder X-ray diffraction (PXRD) pattern of Compound 1.
  • test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the starting materials and reagents shown are all commercially available.
  • Zinc bromide (2.7 g) and lithium bromide (1.04 g) were added with n-butyl ether (20 mL), heated to 50 ° C for 4 h, and cooled for use.
  • 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (8 mL) and n-butyl ether (5 mL) under nitrogen, cooled to 0 ° C, and 0.61 mol/L was added dropwise.
  • the calibration method of the concentration of the prepared organic zinc reagent accurately weighed iodine (1 mmol), placed in a three-necked flask, replaced nitrogen, and added anhydrous 0.5 mol/L LiCl tetrahydrofuran solution (5 mL), stirred and dissolved, and cooled to 0 ° C.
  • the prepared organozinc reagent was slowly added dropwise until the color of the brownish yellow solution disappeared.
  • Zinc bromide (2.25 g) and lithium bromide (0.87 g) were added with n-butyl ether (30 mL), heated to 50 ° C for 2 h, and cooled for use.
  • 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (10 mL) and n-butyl ether (10 mL) under nitrogen, cooled to -20 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (14mL), control the internal temperature does not exceed -10 ° C, after the completion of the addition, the temperature is incubated at -20 ° C for 0.5 h, adding the above-mentioned spare zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at 20 ° C for 3 h.
  • Zinc bromide (3.38 g) and lithium bromide (1.3 g) were added with n-butyl ether (40 mL), heated to 50 ° C for 2 h, and cooled for use.
  • 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (20 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -50 ° C, and slowly added dropwise 2.5 mol / L-butyllithium hexane solution (8mL), control the internal temperature does not exceed -30 ° C, after the addition is completed, the reaction is kept at -50 ° C for 10 h, adding the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution, The reaction was stirred at -20 ° C for 10 h.
  • N-butyl ether (50 mL) was added to zinc iodide (3.19 g) and lithium iodide (1.34 g), and the mixture was heated to 50 ° C for 1.5 h, and cooled for use.
  • 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -60 ° C, and slowly added dropwise 1.6 mol / L-n-hexyl lithium n-hexane solution (13.8mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -60 ° C for 5 h, and the above-mentioned alternate zinc iodide and lithium iodide n-butyl ether solution is added.
  • Zinc bromide (4.5 g) and lithium bromide (1.74 g) were added with n-butyl ether (60 mL), heated to 50 ° C for 3 h, and cooled for use.
  • 4-(2-Chloro-5-bromo-benzyl) phenyl ether (6.513 g) was added with toluene (15 mL) and n-butyl ether (5 mL) under nitrogen, cooled to -30 ° C, and slowly added dropwise 2.5 mol / L-butyllithium n-hexane solution (8.4mL), control the internal temperature does not exceed -20 ° C, after the addition is completed, the reaction is kept at -30 ° C for 3 h, and the above-mentioned alternate zinc bromide and lithium bromide n-butyl ether solution is added.
  • reaction was incubated at -5 ° C for 4 h, and a solution of 2,3,4,6-tetra-O-pivaloyl- ⁇ -D-bromoglucopyranose (14.49 g) in toluene (50 mL) was added and heated to 120 ° C for stirring.
  • Methyl bromide (40 mL) was added to zinc bromide (2.25 g) and lithium bromide (0.87 g), and the mixture was heated to 50 ° C for 3 h, and cooled for use.
  • 4-(2-Chloro-5-iodo-benzyl) phenyl ether (7.45 g) was added with toluene (15 mL), methyl tert-butyl ether (15 mL), cooled to -40 ° C, and slowly added dropwise.
  • the crystal form of the obtained product was subjected to thermogravimetric analysis (TGA) by a Universal V4.7A TA instrument, and the TGA curve (Fig. 1) showed a weight loss of about 18.52% from about room temperature to about 240 ° C.
  • TGA thermogravimetric analysis
  • Fig. 1 The original form Ia crystal form
  • the TGA plot shows a value of 18.7%.
  • the crystal form of the obtained product was subjected to differential scanning calorimetry (DSC) by a Universal V4.7A TA instrument, and the DSC curve (Fig. 2) showed endotherm in the range of about 60 ° C to 85 ° C.
  • the DSC plot shows a range of approximately 50 ° C to 78 ° C.
  • the crystal form of the obtained product was examined by a Bruker D8advance instrument for powder X-ray diffraction (PXRD), and the 2X value of the PXRD pattern (Fig. 3) (CuK ⁇ ). There are characteristic peaks at 3.749°, 7.52°, 7.995°, 8.664°, 15.134°, 15.708°, 17.069°, 18.946°, 20.049°, which are completely consistent with the characteristic peaks of the PXRD pattern of the Ia crystal form in the original patent.
  • PXRD powder X-ray diffraction
  • the crystal form of the product (Compound 1) obtained by the present invention is consistent with the pharmaceutically acceptable crystalline form Ia reported in the original patent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un eutectique de la dapagliflozine, comprenant : 1) l'utilisation d'un halogénure de 4-chloro-3-(4-éthoxybenzyl)phénylique (6) en tant que matière première, la réaction (6) avec de l'alkylidène de lithium et un sel de zinc par l'intermédiaire d'une réaction d'échange X/Li/Zn dans un solvant approprié pour préparer un réactif organate-zinc et du bis[4-chloro-3-(4-éthoxybenzyle)phényle]zinc, puis sa réaction avec du 2,3,4,6-tétra-O-pivaloyl-α-D-bromoglucopyranose (4) par une réaction de substitution nucléophile pour préparer un composé (3); et 2) l'élimination du groupe protecteur pivaloyle du composé (3) pour obtenir de la dapagliflozine (2), et sa réaction directe avec du (S)-1,2-propanediol et de l'eau dans un solvant approprié pour préparer un eutectique de la dapagliflozine (1). La voie de synthèse est comme suit : formule (I). Dans la formule, X dans l'halogénure de 4-chloro-3-(4-éthoxybenzyl)phénylique (6) est choisi parmi Br ou I. Les réactifs utilisés sont tous des réactifs en vrac classiques, bon marché et facilement accessibles, la voie est simplifiée, le coût de la voie est fortement réduit, le rendement et la pureté du produit sont relativement élevés, et les produits ne contiennent pas de diastéréoisomères, et sont appropriés pour une production industrielle.
PCT/CN2017/086106 2016-05-30 2017-05-26 Procédé de préparation de matière eutectique de la dapagliflozine WO2017206808A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610369792 2016-05-30
CN201610369792.9 2016-05-30

Publications (1)

Publication Number Publication Date
WO2017206808A1 true WO2017206808A1 (fr) 2017-12-07

Family

ID=60479663

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/086106 WO2017206808A1 (fr) 2016-05-30 2017-05-26 Procédé de préparation de matière eutectique de la dapagliflozine

Country Status (2)

Country Link
CN (1) CN107445932A (fr)
WO (1) WO2017206808A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113620986A (zh) * 2021-08-17 2021-11-09 沧州那瑞化学科技有限公司 用D-葡萄糖酸-δ-内酯合成治疗糖尿病药物的方法
CN114716425A (zh) * 2022-04-11 2022-07-08 沧州那瑞化学科技有限公司 芳香杂环取代亚甲基的化合物的合成方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109111490B (zh) * 2018-08-09 2021-02-23 浙江大学 卤代新戊酰基吡喃葡萄糖及其用于sglt2抑制剂的制备方法
CN109456315A (zh) * 2018-11-21 2019-03-12 上海大学 碳-芳基糖苷类sglt-2抑制剂前体及其合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101479287A (zh) * 2006-06-28 2009-07-08 布里斯托尔-迈尔斯斯奎布公司 作为用于治疗糖尿病的sglt2抑制剂的(1s)-1,5-脱水-l-c-(3-((苯基)甲基)苯基)-d-葡萄糖醇衍生物与氨基酸的结晶溶剂合物和络合物
CN104496952A (zh) * 2014-11-28 2015-04-08 深圳翰宇药业股份有限公司 一种达格列净的合成方法
CN105153137A (zh) * 2015-09-17 2015-12-16 上海应用技术学院 一种艾格列净的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104829572B (zh) * 2014-02-10 2019-01-04 江苏豪森药业集团有限公司 达格列净新晶型及其制备方法
CN105399735A (zh) * 2015-12-29 2016-03-16 上海应用技术学院 一种艾格列净中间体及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101479287A (zh) * 2006-06-28 2009-07-08 布里斯托尔-迈尔斯斯奎布公司 作为用于治疗糖尿病的sglt2抑制剂的(1s)-1,5-脱水-l-c-(3-((苯基)甲基)苯基)-d-葡萄糖醇衍生物与氨基酸的结晶溶剂合物和络合物
CN104496952A (zh) * 2014-11-28 2015-04-08 深圳翰宇药业股份有限公司 一种达格列净的合成方法
CN105153137A (zh) * 2015-09-17 2015-12-16 上海应用技术学院 一种艾格列净的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN DEJIN ET AL., CHINA MASTER'S THESES FULL-TEXT DATABASE, ENGINEERING TECHNOLOGY I, vol. B016-731, no. 3, 15 March 2016 (2016-03-15) *
LEMAIRE S. ET AL.: "Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents", PURE APPL. CHEM., vol. 86, no. 3, 4 March 2014 (2014-03-04), pages 329 - 333 *
LEMAIRE S. ET AL.: "Stereoselective C-Glycosylation Reactions with Arylzinc Reagents", ORGANIC LETTERS, vol. 14, no. 6, 2 March 2012 (2012-03-02), pages 1480 - 1483, XP055069093 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113620986A (zh) * 2021-08-17 2021-11-09 沧州那瑞化学科技有限公司 用D-葡萄糖酸-δ-内酯合成治疗糖尿病药物的方法
CN113620986B (zh) * 2021-08-17 2024-01-02 沧州那瑞化学科技有限公司 用D-葡萄糖酸-δ-内酯合成治疗糖尿病药物的方法
CN114716425A (zh) * 2022-04-11 2022-07-08 沧州那瑞化学科技有限公司 芳香杂环取代亚甲基的化合物的合成方法
CN114716425B (zh) * 2022-04-11 2023-09-01 沧州那瑞化学科技有限公司 芳香杂环取代亚甲基的化合物的合成方法

Also Published As

Publication number Publication date
CN107445932A (zh) 2017-12-08

Similar Documents

Publication Publication Date Title
WO2017206808A1 (fr) Procédé de préparation de matière eutectique de la dapagliflozine
US9024010B2 (en) Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
JP2021530505A (ja) フェニルピペリジニルインドール誘導体を調製する化学的プロセス
JP2018135384A (ja) １−シアノ−２−（４−シクロプロピル−ベンジル）−４−（β−Ｄ−グルコピラノース−１−イル）−ベンゼンの結晶性錯体、その調製方法及び薬物を調製するためのその使用
CA2472776C (fr) Procede de preparation d'inhibiteurs de reductase hmg-coa
EA016650B1 (ru) Способ асимметрического алкилирования карбонильной группы
WO2015181692A1 (fr) Procédé de préparation de canagliflozine
CN106349138A (zh) 用于制备前列腺素酰胺的新的方法
CN108675976A (zh) 一种6-卤代葡萄糖碳苷及其制备方法和应用
TW202321190A (zh) (s)-4-氯-2-胺基丁酸鹽酸鹽及(s)-4-氯-2-胺基丁酸酯的製備方法
WO2016173551A1 (fr) Procédé de préparation d'ipragliflozine
ES2325266T3 (es) Sintesis de prostaglandina.
HUT68255A (en) Process for the preparation of beta-phenylisoserine derivatives and use thereof
CN111559967B (zh) 一种4-氨基-2-羟基-3-异丙氧基苯甲酸的合成方法
CN111440154B (zh) 一种替格列汀二聚体杂质的合成方法
JP2021517903A (ja) ヘキサヒドロフロフラノール誘導体の調製方法、ヘキサヒドロフロフラノール誘導体の中間体、およびその調製方法
JP5485138B2 (ja) エチニルチミジン化合物の精製方法
IL49286A (en) 1-iodo-1-trans-alkenes their preparation and pharmaceutical compositions containing them
CN111961083B (zh) 一种孟鲁司特钠中间体化合物
JP4667593B2 (ja) ２−アルキル−２−アダマンチル（メタ）アクリレート類の製造法
US4064259A (en) Thiazole cardiovascular agents
CN114195712A (zh) 一种能够用来制备盐酸丙卡特罗的中间体及其制备方法
CN111072450A (zh) 一种烯丙醇类衍生物的合成方法
CN109096270A (zh) 一种卡格列净4-位异构体杂质及其制备方法
CN114213323B (zh) 一种盐酸丙卡特罗的合成新工艺

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17805753

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 15/03/2019)

122 Ep: pct application non-entry in european phase

Ref document number: 17805753

Country of ref document: EP

Kind code of ref document: A1