CN116283513A - Preparation method of dapagliflozin intermediate ortho-isomer impurity - Google Patents
Preparation method of dapagliflozin intermediate ortho-isomer impurity Download PDFInfo
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 23
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000012535 impurity Substances 0.000 title claims abstract description 17
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000006203 ethylation Effects 0.000 claims abstract description 8
- 238000006200 ethylation reaction Methods 0.000 claims abstract description 8
- 230000009467 reduction Effects 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 230000008707 rearrangement Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- 238000000034 method Methods 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 14
- -1 5-bromo-2-chlorobenzoic acid phenyl ester Chemical compound 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- LEWYCBRUDUVOLG-UHFFFAOYSA-N 1,1,2,2-tetrafluoro-2-(1,1,2,2,3,3,4,4-octafluoro-4-iodobutoxy)ethanesulfonyl fluoride Chemical compound FC(F)(I)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(F)(=O)=O LEWYCBRUDUVOLG-UHFFFAOYSA-N 0.000 claims description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000006462 rearrangement reaction Methods 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 5
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims description 4
- 229940008406 diethyl sulfate Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- UHUUYVZLXJHWDV-UHFFFAOYSA-N trimethyl(methylsilyloxy)silane Chemical compound C[SiH2]O[Si](C)(C)C UHUUYVZLXJHWDV-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 229960000346 gliclazide Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- ZUNCHZBITMUSRD-UHFFFAOYSA-N 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene Chemical compound C1=CC(OCC)=CC=C1CC1=CC(Br)=CC=C1Cl ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- GOADIQFWSVMMRJ-UPGAGZFNSA-N dapagliflozin propanediol monohydrate Chemical compound O.C[C@H](O)CO.C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl GOADIQFWSVMMRJ-UPGAGZFNSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000009519 fu-yuan Substances 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- 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
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Abstract
The invention provides a preparation method of dapagliflozin intermediate ortho-isomer impurities, which comprises the following steps: 5-bromo-2-chlorobenzoic acid is used as a starting material, and 5-bromo-2-chloro-2' -ethoxydiphenylmethane which reaches the o-isomer impurity of the gliclazide intermediate is obtained through chlorination, condensation, rearrangement, ethylation and reduction, so that a basis is provided for researching related substances of the dapagliflozin bulk drug.
Description
Technical Field
The invention belongs to the technical field of preparation of dapagliflozin, and particularly relates to a preparation method of an ortho-isomer impurity of a dapagliflozin intermediate.
Background
Dapagliflozin propylene glycol-hydrate was co-developed by Bai-Mei-Shi-Guibao (Bristol-MyersSquibb, BMS) and Aspirin (AstraZeneca, AZ), and dapagliflozin drug substance was first approved by European EMA 11/2012, and was also the first approved type 2 diabetes SGLT2 inhibitor worldwide; us FDA approval was obtained on day 1 and 8 of 2014. Japanese PMDA was approved for sale on 24 days 3.2014; the Chinese NMPA is approved for marketing in 3 and 13 days 2017. At present, a plurality of domestic enterprises apply novel 4-declaration dapagliflozin bulk drug imitation preparations, wherein Shandong Lukang and Beijing Fuyuan imitation drugs are approved to be marketed.
Since dapagliflozin intermediate 5-bromo-2-chloro-4' ethoxydiphenylmethane is prepared, the use of friedel-crafts reaction produces ortho-isomer:
the ortho isomer can be continuously derived in the preparation process of the follow-up raw material medicine to obtain the ortho isomer of the dapagliflozin raw material medicine:
therefore, the ortho-isomer impurity of the intermediate is of great significance to the research of dapagliflozin bulk drug.
Disclosure of Invention
The invention aims to provide a preparation method of dapagliflozin intermediate ortho-isomer impurities, and the preparation method is used for detecting the dapagliflozin intermediate ortho-isomer impurities, and has important theoretical and practical application values.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a preparation method of dapagliflozin intermediate ortho-isomer impurity, comprising the following steps:
s1, chloro: adding 5-bromo-2-chloro-benzoic acid into an organic solvent, adding a chloro reagent, and heating to react to prepare a compound I, namely 5-bromo-2-chloro-benzoyl chloride;
s2, condensation: condensing 5-bromo-2-chloro-benzoyl chloride with phenol to prepare a compound II, namely 5-bromo-2-chlorobenzoic acid phenyl ester, using triethylamine as an acid binding agent, and crystallizing the solution into absolute ethyl alcohol;
s3, rearrangement: dissolving 5-bromo-2-chlorobenzoic acid phenyl ester in anhydrous dichloromethane, uniformly mixing with aluminum chloride, removing dichloromethane under reduced pressure, and heating the solid to perform rearrangement reaction;
s4, column chromatography: dissolving the rearrangement reaction product with dichloromethane, adding ethyl acetate to increase the solubility of the product, and performing column chromatography purification after finishing post-treatment, wherein the eluent is at least one of ethyl acetate, cyclohexane and n-hexane;
s5, ethylation: ethylating the compound III-b obtained by column chromatography to prepare a compound IV;
s6, reduction: the ethylation product is reduced by using triethylsilane or tetramethyl disiloxane as a reducing agent, lewis acid is boron trifluoride diethyl ether or aluminum trichloride, and methylene dichloride, acetonitrile or toluene are used as solvents to obtain a target compound V5-bromo-2-chloro-2' -ethoxydiphenylmethane, wherein the specific synthetic route is as follows:
further, in the step S1, the chloro reagent is one of oxalyl chloride and thionyl chloride, the catalyst is DMF, the organic solvent is dichloromethane or dichloroethane, the reaction temperature is 20-50 ℃, and the molar ratio of the chloro reagent to 5-bromo-2 chloro-benzoic acid is 1.2-3:1.
Further, in the step S2, the molar ratio of phenol to 5-bromo-2-chloro-benzoyl chloride is 1.2-1.5:1, and the reaction temperature is-5-20 ℃.
Further, the temperature of the reaction in the step S3 is 80-120 ℃.
Further, in the step S4, the eluent is ethyl acetate and the cyclohexane volume ratio is 1:30 for elution.
Further, in the step S5, one of polar aprotic solvents such as acetone, tetrahydrofuran and DMF is used, the selected base is one of sodium carbonate and potassium carbonate, the selected ethylating reagent is one of diethyl sulfate and bromoethane, and the selected catalyst is one of sodium iodide and potassium iodide.
Further, in the step S6, a mixed solvent of dichloromethane and acetonitrile is preferable, and the reaction temperature is 30-55 ℃.
The invention has the advantages that: according to the invention, 5-bromo-2-chlorobenzoic acid is used as a starting material, a chloro reagent is used for preparing 5-bromo-2-chlorobenzoyl chloride, phenol is condensed into phenolic ester, the phenolic ester is rearranged to obtain an ortho-para mixture, an ortho-position product is separated through column purification and ethylation, and then target compound 5-bromo-2-chloro-2' -ethoxydiphenylmethane is obtained through reduction, so that the whole reaction process is simple and easy to control, and a basis is provided for researching related substances of dapagliflozin bulk drug.
Drawings
FIG. 1 is an HPLC chart of Compound II in an embodiment of the invention;
FIG. 2 is a central control HPLC plot of compounds III-a and III-b in an embodiment of the invention;
FIG. 3 is an HPLC plot of compound III-b after column purification in an embodiment of the invention;
FIG. 4 is an HPLC plot of Compound IV in an embodiment of the invention;
FIG. 5 is an HPLC plot of Compound V in an embodiment of the invention;
Detailed Description
In the following examples, HPLC analysis was performed using the following methods:
chromatographic column: the Epider Hypersil ODS2, 4.6mm.times.150mm, 5 μm or equivalent chromatography column, flow rate 1.0mL/min, column Wen, elution time 40min, mobile phase: acetonitrile: water=60:40, purified water was adjusted to pH 3.0 with glacial acetic acid, mixed well with chromatographic acetonitrile and degassed for use.
A preparation method of dapagliflozin intermediate ortho-isomer impurity comprises the following steps:
step one, chloro
Adding 5-bromo-2-chloro-benzoic acid into an organic solvent, adding a chloro reagent, heating for reaction, wherein the molar ratio of the chloro reagent to the 5-bromo-2-chloro-benzoic acid is (1.2-3) 1, the chloro reagent is oxalyl chloride or thionyl chloride, the catalyst is DMF, the mailing solvent is dichloromethane or dichloroethane, and the reaction temperature is 20-50 ℃.
Step two, condensation
Condensing the 5-bromo-2-chloro-benzoyl chloride obtained in the first step with phenol, wherein the molar ratio of the phenol to the 5-bromo-2-chloro-benzoyl chloride is (1.2-1.5): 1, the reaction temperature is-5 ℃ to 20 ℃, triethylamine is used as an acid-binding agent, and the used crystallization solvent is absolute ethyl alcohol.
Step three, rearrangement
Rearranging the phenyl 5-bromo-2-chlorobenzoate obtained in the step two, preferably using aluminum chloride for catalysis, using anhydrous dichloromethane to dissolve the phenyl 5-bromo-2-chlorobenzoate, uniformly mixing with the aluminum chloride, removing the dichloromethane under reduced pressure, heating the solid for rearranging reaction, wherein the reaction temperature is 80-120 ℃.
Step four, column chromatography
Quenching the rearrangement reaction product obtained in the third step after organic dissolution, preferably using dichloromethane to dissolve, adding ethyl acetate to increase the solubility of the product, and performing column chromatography purification after finishing the post-treatment, wherein the eluent is at least one of ethyl acetate, cyclohexane and n-hexane, preferably the eluent is ethyl acetate and cyclohexane in a volume ratio of 1:30 for eluting.
Step five, ethylation
And (3) ethylating the compound III-b obtained by purification in the step (IV), wherein preferably one of polar aprotic solvents such as acetone, tetrahydrofuran and DMF is used, inorganic alkali such as sodium carbonate and potassium carbonate is used, ethylating reagents such as diethyl sulfate and bromoethane are used, and catalysts such as sodium iodide and potassium iodide are used.
Step six, reduction
The ethylation product of step five is reduced, preferably using triethylsilane or tetramethyldisiloxane as reducing agent, using boron trifluoride etherate or aluminum trichloride as lewis acid, preferably using dichloromethane and acetonitrile as solvents, at a reaction temperature of 30-55deg.C.
The specific detailed preparation steps are as follows:
preparation of Compound I:
method 1:
5-bromo-2-chloro-benzoic acid (30 g,0.128mol,1.0 eq), thionyl chloride (31.83 g,0.267mol,2.1 eq) and dichloromethane (250 mL) were added to a glass bottle equipped with a stirrer and a thermometer, 2 drops of N, N-dimethylformamide were added, the mixture was refluxed at 40℃for 4 hours, and after the reaction was completed, the mixture was concentrated to dryness to obtain 33.8g of pale yellow liquid, the yield was 104.3%, and 30mL of dichloromethane was added to dissolve and store the mixture for later use.
Method 2: method 2 differs from method 1 in that: the chloro reagent was oxalyl chloride (11.18 g,0.153mol,1.2 eq), and was refluxed at 35℃and concentrated to dryness after the reaction to give 33g of pale yellow liquid, with a yield of 102.3%.
Preparation of Compound II:
method 1: phenol (14.39 g,0.153mol,1.2 eq) and triethylamine (19.34 g,0.191mol,1.5 eq) methylene dichloride (250 mL) are added into a glass bottle provided with a stirrer and a thermometer, the temperature is reduced below-5 ℃, a methylene dichloride solution of the compound I is started to be dropwise added, the temperature is controlled to be not higher than 0 ℃, the mixture is cooled to room temperature for reaction for 3 hours after the dropwise addition is completed, the liquid phase is detected, the 5-bromo-2-chlorobenzoic acid is not continuously converted, the temperature is reduced below 0 ℃, water quenching is added, layering is carried out, an organic layer is washed with 250mL of water, layering is carried out, 20g of anhydrous sodium sulfate is added into the organic layer, after drying, methylene dichloride is recovered to obtain light yellow solid, 80mL of absolute ethyl alcohol is added for heating and dissolving, the solid is cooled, the solid is separated, and after filtering, the mixture is dried by blast at 30 ℃ to obtain 33.83g of white solid 5-bromo-2-chlorobenzoic acid phenyl ester with the yield of 84.1%. Method 2: method 2 differs from method 1 in that: phenol (16.79 g,0.153mol,1.4 eq) and triethylamine (21.92 g,0.216mol,1.7 eq) were added to the mixture, the organic layer was washed with 300mL of water, and after filtration, 31.38g of a white solid, phenyl 5-bromo-2-chlorobenzoate, was obtained in a yield of 79.2% by air drying at 30 ℃.
Rearrangement reaction:
method 1: adding compound II 5-bromo-2-chlorobenzoic acid phenyl ester (30 g,0.096mol,1.0 eq) into a single-neck flask, adding 100mL of anhydrous dichloromethane to dissolve and clarify, adding anhydrous aluminum chloride (25.68 g,0.193mol,2.0 eq) in batches under reduced temperature, removing dichloromethane by vacuum distillation at the temperature below 30 ℃ to obtain pale yellow solid, replacing 3 times with nitrogen, placing under an oil bath pot at 85 ℃ to react for 10h, gradually changing the solid in the flask into reddish brown, obtaining a mixture of the compounds III-a and III-b, cooling to room temperature, sampling, detecting liquid phase, wherein the peak areas of the compounds III-a and III-b are 67.9% and 22.7%, and the residue of the compound II is about 5.2%.
Method 2: method 2 differs from method 1 in that: the oil bath reaction temperature is 95 ℃, the peak areas of the compound III-a and the compound III-b are 56.1 percent and 34.2 percent respectively, and the residue of the compound II is about 3.7 percent.
Method 3: method 3 differs from method 1 in that: the oil bath reaction temperature is 110 ℃, the peak areas of the compound III-a and the compound III-b are respectively 51.62 percent and 45.7 percent, and the residue of the compound II is about 2.2 percent.
Method 4: method 2 differs from method 1 in that: the oil bath reaction temperature is 120 ℃, the peak areas of the compound III-a and the compound III-b are 49.45 percent and 42.7 percent respectively, and the residue of the compound II is about 2.5 percent.
Column chromatography:
method 1: to a single-port flask of a rearrangement reaction product of 5-bromo-2-chlorobenzoic acid phenyl ester (30 g,0.096mol,1.0 eq) was added 300mL of anhydrous dichloromethane, stirred at 20 to 30℃for 5 hours to gradually dissolve the solid, a dichloromethane solution was poured into 200g of ice water to quench, ethyl acetate 30mL was added, the solid was stirred to dissolve and then separated, an organic layer was brownish red and opaque liquid was separated, the organic layer was further washed with 200mL of water, dried with 20g of anhydrous sodium sulfate and then evaporated under reduced pressure to give a brown oil, this oil was subjected to column chromatography, the eluent was ethyl acetate-n-hexane in a volume ratio of 1:30, the silica gel column was first washed with n-hexane, the eluent was gradually added in a volume ratio of 1:30, the preceding fraction was collected as III-b, the eluent was evaporated under reduced pressure to give a pale yellow solid, and ethyl acetate-n-hexane in a volume ratio of 1:40 was used again for 30mL to conduct beating purification to give a white solid compound III-11.7 g, yield 39%.
Method 2: method 2 differs from method 1 in that: the ethyl acetate was used in an amount of 40mL to give 10.2g of the compound III-b as a white solid in 34% yield.
Preparation of compound IV:
method 1:
in a glass bottle equipped with a stirrer and a thermometer, compound III-b (10 g,0.032mol,1.0 eq) was added, 150mL of acetone was added, stirring was performed to dissolve compound III-b, anhydrous sodium carbonate (10.21 g,0.96mol,1.2 eq) was added, sodium iodide (0.9 g,0.06mol,0.2 eq) was added, dropwise addition of diethyl sulfate (5.3 g,0.034mol,1.07 eq) was started at a temperature of not higher than 0 ℃, the dropwise addition was completed, the reaction was allowed to proceed to room temperature for 6 hours, the conversion of III-b was completed, the reaction solution was cooled to below-5 ℃, 100mL of water was added to quench, stirring was performed for 10min for delamination, the aqueous layer was extracted with 200mL of methylene chloride, delamination was combined with an organic layer, washing with 100mL of water, 20g of anhydrous sodium sulfate was added to dry and then filtered, the filtrate was evaporated under reduced pressure to obtain a pale yellow liquid, 20mL of absolute ethyl alcohol was added to evaporate to dryness, a cloudy liquid was obtained, 60 ℃ was added, the solid was cooled to be precipitated at a temperature of 60 ℃, the solid was cooled to be dried, and 1.8.8% of white solid was obtained, and a solid was cooled under vacuum condition was obtained.
Method 2:
Preparation of Compound V:
method 1:
adding compound IV (20 g,0.059mol,1.0 eq) into a glass bottle with a stirrer and a thermometer, adding 160mL of methylene dichloride, stirring to dissolve the compound IV, cooling to-10 ℃, adding anhydrous aluminum chloride (9.42 g,0.07mol,1.2 eq) in batches, controlling the temperature to be not higher than 0 ℃, completing the addition of the anhydrous aluminum chloride, cooling to about-10 ℃, starting to dropwise add tetramethyl disiloxane (9.5 g,0.7mol,1.2 eq), controlling the temperature to be not higher than 5 ℃ in the dropwise adding process, controlling the temperature to be 0 to 5 ℃ after dropwise adding, reacting for 6 hours after liquid phase detection IV conversion is completed, cooling the reaction liquid to below-10 ℃, pouring into 250mL of ice water for quenching, stirring for 10min, layering, extracting the water layer by using 100mL of dichloromethane, layering, combining the organic layers, washing by using 100mL of water, washing by using 120mL of saturated sodium bicarbonate, adding 20g of anhydrous sodium sulfate, drying, filtering, evaporating the filtrate under reduced pressure to remove the solvent to obtain a pale yellow liquid, adding 100mL of n-heptane, stirring for 1h at room temperature, filtering at room temperature to remove insoluble matters, evaporating the filtrate under reduced pressure to remove the n-heptane, adding 20mL of absolute ethyl alcohol, steaming to dryness to obtain a turbid liquid, adding 60mL of absolute ethyl alcohol, cooling to-10 ℃, pulping and stirring at the temperature of minus 10 ℃, precipitating a solid, filtering, and drying at the temperature of 25 ℃ in vacuum to obtain 14.5g of an off-white solid compound V, wherein the yield is 75.59%.
Method 2:
Method 3:
method 3 differs from method 1 in that: the solvent is dichloromethane 150mL, acetonitrile 50mL, triethylsilane (26.75 g,0.189mol,3.2 eq) is added, boron trifluoride diethyl ether (13.7 g,0.117mol,2.0 eq) is added, after the addition, reflux reaction is carried out for 4h at a temperature of 35 to 45 ℃, after the conversion of IV is detected, precipitation is generated, the reaction solution is cooled to below-10 ℃, 250mL of 15% saturated sodium carbonate aqueous solution is added for quenching, stirring is carried out for 30min, so that the solid is dissolved and layered, the aqueous layer is extracted by 100mL of dichloromethane, layering, the organic layers are combined, washing by 100mL of water, drying by adding anhydrous sodium sulfate 20g, filtering is carried out, the filtrate is subjected to reduced pressure evaporation to remove the solvent, the obtained yellow oily matter is added, 100mL of n-heptane is added, stirring is carried out for 1h at room temperature, insoluble matters are removed by filtration at room temperature, n-heptane is removed by reduced pressure evaporation, 20mL of absolute ethyl alcohol is added until the absolute liquid is obtained, 60mL of absolute ethyl alcohol is added, stirring is carried out until the absolute ethyl alcohol is cooled to below-10 ℃, the solid is separated, filtering is carried out, vacuum drying is carried out at 25 ℃, and the white class compound 16.37g is obtained, yield is 85.37%.
Method 4:
Claims (7)
1. A method for preparing dapagliflozin intermediate ortho-isomer impurities, which is characterized by comprising the following steps:
s1, chloro: adding 5-bromo-2-chloro-benzoic acid into an organic solvent, adding a chloro reagent, and heating to react to prepare a compound I, namely 5-bromo-2-chloro-benzoyl chloride;
s2, condensation: condensing 5-bromo-2-chloro-benzoyl chloride with phenol to prepare a compound II, namely 5-bromo-2-chlorobenzoic acid phenyl ester, using triethylamine as an acid binding agent, and crystallizing the solution into absolute ethyl alcohol;
s3, rearrangement: dissolving 5-bromo-2-chlorobenzoic acid phenyl ester in anhydrous dichloromethane, uniformly mixing with aluminum chloride, removing dichloromethane under reduced pressure, and heating the solid to perform rearrangement reaction;
s4, column chromatography: dissolving the rearrangement reaction product with dichloromethane, adding ethyl acetate to increase the solubility of the product, and performing column chromatography purification after finishing post-treatment, wherein the eluent is at least one of ethyl acetate, cyclohexane and n-hexane;
s5, ethylation: ethylating the compound III-b obtained by column chromatography to prepare a compound IV;
s6, reduction: the ethylation product is reduced by using triethylsilane or tetramethyl disiloxane as a reducing agent, lewis acid is boron trifluoride diethyl ether or aluminum trichloride, and methylene dichloride, acetonitrile or toluene are used as solvents to obtain a target compound V5-bromo-2-chloro-2' -ethoxydiphenylmethane, wherein the specific synthetic route is as follows:
2. a process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: in the step S1, the chloro reagent is one of oxalyl chloride and thionyl chloride, the catalyst is DMF, the organic solvent is dichloromethane or dichloroethane, the reaction temperature is 20-50 ℃, and the molar ratio of the chloro reagent to 5-bromo-2 chloro-benzoic acid is 1.2-3:1.
3. A process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: in the step S2, the molar ratio of phenol to 5-bromo-2-chloro-benzoyl chloride is 1.2-1.5:1, and the reaction temperature is-5-20 ℃.
4. A process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: the temperature of the reaction in the step S3 is 80-120 ℃.
5. A process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: and in the step S4, eluting by using ethyl acetate and cyclohexane with the volume ratio of 1:30.
6. A process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: in the step S5, one of polar aprotic solvents such as acetone, tetrahydrofuran and DMF is used, the selected alkali is one of sodium carbonate and potassium carbonate, the selected ethylating reagent is one of diethyl sulfate and bromoethane, and the selected catalyst is one of sodium iodide and potassium iodide.
7. A process for the preparation of dapagliflozin intermediate ortho-isomer impurities according to claim 1, characterised in that: in the step S6, a mixed solvent of dichloromethane and acetonitrile is preferable, and the reaction temperature is 30-55 ℃.
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| 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 |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN114315534A (en) * | 2021-12-31 | 2022-04-12 | 山东鲁宁药业有限公司 | Preparation method of dapagliflozin intermediate |
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| 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 |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN114315534A (en) * | 2021-12-31 | 2022-04-12 | 山东鲁宁药业有限公司 | Preparation method of dapagliflozin intermediate |
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| CN117658784A (en) * | 2023-12-30 | 2024-03-08 | 山东诚汇双达药业有限公司 | Preparation method of dapagliflozin intermediate |
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