CN111253346A - Synthetic method for preparing empagliflozin intermediate - Google Patents
Synthetic method for preparing empagliflozin intermediate Download PDFInfo
- Publication number
- CN111253346A CN111253346A CN202010248129.XA CN202010248129A CN111253346A CN 111253346 A CN111253346 A CN 111253346A CN 202010248129 A CN202010248129 A CN 202010248129A CN 111253346 A CN111253346 A CN 111253346A
- Authority
- CN
- China
- Prior art keywords
- compound
- solvent
- reaction
- water
- dichloromethane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 8
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 8
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 13
- 238000005406 washing Methods 0.000 claims abstract description 13
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010791 quenching Methods 0.000 claims abstract description 10
- 230000000171 quenching effect Effects 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract 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 abstract description 8
- 230000010933 acylation Effects 0.000 claims abstract description 8
- 238000005917 acylation reaction Methods 0.000 claims abstract description 8
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000005416 organic matter Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003849 aromatic solvent Substances 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 5
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000003983 crown ethers Chemical class 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 8
- 238000003786 synthesis reaction Methods 0.000 claims 8
- 150000003990 18-crown-6 derivatives Chemical group 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HUNLNKBDQXGMAP-INIZCTEOSA-N (3s)-3-[4-[(5-bromo-2-chlorophenyl)methyl]phenoxy]oxolane Chemical compound ClC1=CC=C(Br)C=C1CC(C=C1)=CC=C1O[C@@H]1COCC1 HUNLNKBDQXGMAP-INIZCTEOSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000002341 toxic gas Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-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
- C07D307/18—Heterocyclic compounds containing five-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
- C07D307/20—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthetic method for preparing an empagliflozin intermediate, which comprises the following process routes:
the method comprises the following specific steps: 1) mixing the compound I with a solvent, preparing a compound II by using an acylation reagent, adding the compound II into a system of fluorobenzene and aluminum trichloride, carrying out Friedel-crafts reaction at room temperature, quenching by using water, separating liquid, washing and concentrating an organic matter to obtain a compound III; 2) adding the compound III into a reaction kettle, adding a solvent, alkali and a catalyst, adding the compound IV, heating for reaction, washing with water after the reaction, concentrating, and crystallizing to obtain a solid compound V; 3) adding the compound V into a reaction kettle, adding a solvent, an acid and a reducing agent, quenching with water after the reaction is finished, separating, washing, concentrating an organic matter, and crystallizing to obtain a solid compound VI. The method has the advantages of simple and safe process, high product yield, easy impurity control and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical intermediates, and particularly relates to a synthetic method for preparing an eprazidine intermediate.
Background
Empagliflozin (Empagliflozin) is a diabetes drug targeting SGLT-2 type targets. The medicine is used for treating type II diabetes patients, and the SGLT-2 type target medicine is a popular field for diabetes research in recent years. (3S) -3- [4- [ (5-bromo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran was used as the most critical starting material for empagliflozin. The quality and production cost thereof occupy an important position in the medicine.
There are many methods for preparing (3S) -3- [4- [ (5-bromo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran, and there are mainly the following two methods:
first, the report from patent US2010/0099641 shows a specific process route:
the method comprises the steps of preparing acyl chloride from a compound 1, carrying out Friedel-crafts reaction on the acyl chloride and anisole, then carrying out demethylation on boron tribromide, reacting the boron tribromide with S-methanesulfonate (a compound 9), and reducing to obtain a target product 6. The synthesis method uses boron tribromide and the reaction at ultralow temperature is not favorable for scale-up production, and the compound 9 is prepared from S-trihydroxy tetrahydrofuran, while S-3-hydroxytetrahydrofuran is not available and expensive. Therefore, the process is not suitable for industrialization.
Secondly, the report from patent CN107652277A shows that the specific process route is as follows:
the method takes a compound 11 as a raw material to synthesize a compound 6, has longer reaction steps and also relates to a bromination process; the potassium tert-butoxide used in the process is flammable and explosive, and meanwhile, the potassium tert-butoxide used in the process has high requirements on moisture, so that a large amount of impurities are easily generated, and the purity and the yield of the product are not ideal. And sodium borohydride belongs to a controlled material, and meanwhile, a large amount of hydrogen is generated by reaction post-treatment, so that high potential safety hazard exists. Therefore, the process is not suitable for industrialization.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method for preparing an epraziquant intermediate, which uses cheap and easily-obtained raw and auxiliary materials, has simple and safe production process, high product yield and easily-controlled impurities and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method for preparing an empagliflozin intermediate comprises the following process route:
more specifically, the synthesis method comprises the following steps:
1) mixing the compound I with a solvent, preparing a compound II by using an acylation reagent, adding the compound II into a system of fluorobenzene and aluminum trichloride, carrying out Friedel-crafts reaction at room temperature, quenching by using water, separating liquid, washing and concentrating an organic matter to obtain a compound III;
2) adding the compound III into a reaction kettle, adding a solvent, alkali and a catalyst, adding 3-hydroxytetrahydrofuran (namely a compound IV), heating for reaction, washing with water after the reaction, concentrating, and crystallizing to obtain a solid compound V;
3) adding the compound V into a reaction kettle, adding a solvent, an acid and a reducing agent, quenching with water after the reaction is finished, separating, washing, concentrating an organic matter, and crystallizing to obtain a solid compound VI.
In step 1):
the solvent is dichloromethane, fluorobenzene or a mixed solvent of the dichloromethane and the fluorobenzene;
the acylating agent is thionyl chloride or oxalyl chloride.
As a preferable scheme:
the solvent is a mixed solvent of dichloromethane and fluorobenzene;
the molar ratio of the total using amount of fluorobenzene to the compound I is 1.5-5: 1, preferably 2-3: 1;
the acylation reagent is preferably thionyl chloride, which can avoid the generation of a large amount of toxic gas carbon monoxide in the acylation process, and the molar ratio of the dosage of the thionyl chloride to the compound I is 1.1-5: 1, preferably 1.2-1.5: 1.
In step 2):
the solvent is aromatic solvent such as tetrahydrofuran, dichloromethane, toluene and xylene, or mixed solvent of one of tetrahydrofuran, dichloromethane and aromatic solvent and water;
the alkali is potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide;
the catalyst is quaternary ammonium salt, crown ether or PEG.
As a preferable scheme:
the solvent is a mixed solvent of toluene and water, the dosage ratio of toluene, water and the compound III is 2-10: 2-5: 1 (volume: mass), and is preferably 3-5: 2-3: 1;
the alkali is sodium hydroxide, the dosage of the sodium hydroxide is 1-5 times of the equivalent of the compound II, and more preferably 1.5-2 times of the equivalent;
the catalyst is 18-crown-6, and the mass ratio of the dosage of the 18-crown-6 to the compound III is 0.01-0.2: 1, preferably 0.05-0.1: 1;
the molar ratio of the consumption of the 3-hydroxytetrahydrofuran (compound IV) to the compound III is 1.05-2: 1, preferably 0.05-0.1: 1;
the reaction temperature is 20-100 ℃, preferably 30-70 ℃.
In step 3):
the solvent is an aromatic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, toluene, xylene and the like, or a mixed solvent of two of tetrahydrofuran, dichloromethane, aromatic solvent and acetonitrile;
the acid is aluminum trichloride, trifluoroacetic acid or glacial acetic acid and the like;
the reducing agent is sodium borohydride, triethylsilane or hydrogen-containing double-end socket.
As a preferable scheme:
the solvent is toluene, the dosage ratio of the toluene to the compound V is 3: 10-1 (volume: mass), and preferably 3-5: 1;
the acid is aluminum trichloride, the reducing agent is hydrogen-containing double-end socket (1,1,3, 3-tetramethyldisiloxane), and the hydrogen-containing double-end socket is milder than sodium borohydride and the like; the molar ratio of the aluminum trichloride to the hydrogen-containing double end socket to the compound is 1-2: 1-3: 1, preferably 1.1-1.5: 1.2-2: 1;
the reaction temperature is 10-40 ℃, preferably 20-30 ℃.
In addition, in the step 2) and the step 3), the reagent used for crystallization is alkanol, alkane or a mixed reagent of alkanol and water, preferably ethanol or isopropanol, and the dosage ratio of the alcohol to the compound III or the compound V is 3-10: 1 (volume: mass), and more preferably 3-5: 1.
The invention has the beneficial effects that:
the invention adopts the conventional alkali and the catalyst for the matching reaction, the reagent is cheap and easy to obtain, and the product purity is high; the reaction temperature of the whole process can be controlled in a lower range, the energy consumption is low, the reaction is mild, and the industrial production is facilitated.
Drawings
FIG. 1 is a HNMR spectrum of example 1 of the present invention.
FIG. 2 is a HPLC chart of example 1 of the present invention.
FIG. 3 is a HPLC chart of example 2 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The basic process routes of the following embodiments are as follows:
example 1
23.7g of Compound I, 100mL of dichloromethane, 0.15g of DMF0, and 17g of thionyl chloride were weighed into a reaction flask, and the mixture was heated under reflux. After the reaction, the mixture was concentrated to dryness. Dichloromethane (20 mL) was added to dissolve the mixture to obtain an acid chloride solution.
Adding 19g of fluorobenzene, 100mL of dichloromethane and 20g of aluminum trichloride into the other reaction bottle, cooling to 0-5 ℃, and adding the acyl chloride preparation solution. After the addition, the reaction is carried out for 8 hours at the temperature of 0-10 ℃, water is added for quenching, and 33g of compound III is obtained after treatment. The purity is 97.2%.
Adding 100mL of toluene, 50mL of water and 3g of 18-crown-6-ether into 30g of the compound III, adding 8g of sodium hydroxide while stirring, adding 16g of the compound IV, heating to 50-60 ℃, reacting for 8 hours, demixing, washing with water, concentrating, adding 150mL of ethanol, dissolving, cooling to 0-10 ℃, and crystallizing to obtain 28.2g of off-white particles of the compound V. The purity was 98.9% and the yield in two steps was 81.3%.
Adding 28g of compound V, 125mL of toluene and 15g of aluminum trichloride into a reaction bottle, dropwise adding 15g of hydrogen-containing double seal head at 20-25 ℃, reacting for three hours at 20-25 ℃, adding water for quenching, layering, washing with water, concentrating, adding 120mL of ethanol, dissolving, and crystallizing at 20-25 ℃ (adding a little seed crystal) to obtain 25.6g of white granular solid of the target compound VI. H-NMR is shown in FIG. 1, purity 99.72% (FIG. 2), yield 95%. Mp 89.5-91.1 ℃.
Example 2
100g of Compound I, 400mL of dichloromethane, 0.7g of DMF, and 70g of thionyl chloride were weighed in a reaction flask, and heated under reflux. After the reaction, the mixture was concentrated to dryness. 100mL of dichloromethane was added to dissolve the resulting solution to obtain an acid chloride solution.
Adding 80g of fluorobenzene, 400mL of dichloromethane and 84g of aluminum trichloride into the other reaction bottle, cooling to 0-5 ℃, and adding the acyl chloride preparation solution. After the reaction is finished at 0-10 ℃, the reaction is carried out for 8 hours, water is added for quenching, and 145g of compound 3 is obtained after treatment. The purity is 96.2%.
Adding 460mL of toluene, 230mL of water and 13g of 18-crown-6-ether into 140g of the compound 3, adding 37g of sodium hydroxide while stirring, adding 75g of the compound IV, heating to 60-65 ℃, reacting for 5 hours, demixing, washing with water, concentrating, adding 250mL of ethanol, dissolving, cooling to 5-10 ℃, and crystallizing to obtain 131.2g of the white-like particles of the compound V. The purity was 99.2%, and the yield in two steps was 84.6%.
Adding 125g of compound V, 560mL of toluene and 63g of aluminum trichloride into a reaction bottle, dropwise adding 67g of hydrogen-containing double end enclosure at 20-25 ℃, reacting at 20-28 ℃ for 4 hours, adding water for quenching, layering, washing with water, concentrating, adding 540mL of ethanol, dissolving, and crystallizing at 5-10 ℃ (adding a little seed crystal) to obtain 113.5g of the white-like granular solid of the target compound VI. Purity 99.75% (fig. 3), yield 94.2%. Mp 89.3-91 ℃.
Compared with the prior art, firstly, the acylation reagent oxalyl chloride is changed into thionyl chloride, so that the generation of a large amount of toxic gas carbon monoxide in the acylation process is avoided; secondly, the conventional alkali and the catalyst are adopted for the reaction, the reagent is cheap and easy to obtain, the reaction is mild, and the product purity is high; thirdly, a mild reducing agent is used to replace dangerous sodium borohydride. The reaction temperature of the whole process is 0-70 ℃, the energy consumption is low, and the industrial production is facilitated.
Claims (10)
1. A synthetic method for preparing an empagliflozin intermediate comprises the following process route:
2. the synthesis method according to claim 1, characterized by comprising in particular the following steps:
1) mixing the compound I with a solvent, preparing a compound II by using an acylation reagent, adding the compound II into a system of fluorobenzene and aluminum trichloride, carrying out Friedel-crafts reaction at room temperature, quenching by using water, separating liquid, washing and concentrating an organic matter to obtain a compound III;
2) adding the compound III into a reaction kettle, adding a solvent, alkali and a catalyst, adding 3-hydroxytetrahydrofuran, heating for reaction, washing with water after the reaction, concentrating, and crystallizing to obtain a solid compound V;
3) adding the compound V into a reaction kettle, adding a solvent, an acid and a reducing agent, quenching with water after the reaction is finished, separating, washing, concentrating an organic matter, and crystallizing to obtain a solid compound VI.
3. The method of synthesis according to claim 2, wherein in step 1):
the solvent is dichloromethane, fluorobenzene or a mixed solvent of the dichloromethane and the fluorobenzene;
the acylating agent is thionyl chloride or oxalyl chloride.
4. The method of synthesis according to claim 2, wherein in step 2):
the solvent is tetrahydrofuran, dichloromethane and aromatic solvent, or a mixed solvent of one of tetrahydrofuran, dichloromethane and aromatic solvent and water;
the alkali is potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide;
the catalyst is quaternary ammonium salt, crown ether or PEG.
5. The method of synthesis according to claim 2, wherein in step 3):
the solvent is tetrahydrofuran, dichloromethane, acetonitrile, an aromatic solvent or a mixed solvent of two of tetrahydrofuran, dichloromethane, an aromatic solvent and acetonitrile;
the acid is aluminum trichloride, trifluoroacetic acid or glacial acetic acid;
the reducing agent is sodium borohydride, triethylsilane or hydrogen-containing double-end socket.
6. The method of synthesis according to claim 2, characterized in that:
in the step 2) and the step 3), the reagent used for crystallization is alkanol, alkane or a mixed reagent of alkanol and water.
7. The method of synthesis according to claim 2, wherein in step 1):
the acylation reagent is thionyl chloride, and the molar ratio of the dosage of the thionyl chloride to the compound I is 1.1-5: 1;
the molar ratio of the using amount of fluorobenzene to the compound I is 1.5-5: 1.
8. The method of synthesis according to claim 2, wherein in step 2):
the solvent is a mixed solvent of toluene and water, and the dosage ratio of the toluene, the water and the compound III is 2-10: 2-5: 1 (volume: mass);
the alkali is sodium hydroxide, and the dosage of the sodium hydroxide is 1-5 times equivalent of that of the compound II;
the catalyst is 18-crown-6, and the mass ratio of the dosage of the 18-crown-6 to the compound III is 0.01-0.2: 1;
the molar ratio of the consumption of the 3-hydroxytetrahydrofuran to the compound III is 1.05-2: 1;
the reaction temperature is 20-100 ℃.
9. The method of synthesis according to claim 2, wherein in step 3):
the solvent is toluene, and the dosage ratio of the toluene to the compound V is 3: 10-1 (volume: mass);
the acid is aluminum trichloride, the reducing agent is a hydrogen-containing double end socket, and the molar ratio of the aluminum trichloride to the hydrogen-containing double end socket to the compound is 1-2: 1-3: 1;
the reaction temperature is 10-40 ℃.
10. The method of synthesis according to claim 2, characterized in that:
in the step 2) and the step 3), the reagent used for crystallization is ethanol or isopropanol, and the dosage ratio of the reagent to the compound III or the compound V is 3-10: 1 (volume: mass).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010248129.XA CN111253346A (en) | 2020-04-01 | 2020-04-01 | Synthetic method for preparing empagliflozin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010248129.XA CN111253346A (en) | 2020-04-01 | 2020-04-01 | Synthetic method for preparing empagliflozin intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111253346A true CN111253346A (en) | 2020-06-09 |
Family
ID=70942612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010248129.XA Pending CN111253346A (en) | 2020-04-01 | 2020-04-01 | Synthetic method for preparing empagliflozin intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111253346A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113666892A (en) * | 2021-09-23 | 2021-11-19 | 浙江宏元药业股份有限公司 | Novel crystal form of empagliflozin intermediate and preparation method thereof |
| CN114773373A (en) * | 2022-04-08 | 2022-07-22 | 浙江普洛家园药业有限公司 | Preparation method of engagliflozin key intermediate and engagliflozin impurity |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| WO2015101916A1 (en) * | 2013-12-30 | 2015-07-09 | Mylan Laboratories Ltd. | Process for the preparation of empagliflozin |
| 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 |
| CN107163033A (en) * | 2017-06-15 | 2017-09-15 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method net high-purity Yi Palie |
| CN108675976A (en) * | 2018-05-14 | 2018-10-19 | 浙江宏元药业股份有限公司 | A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application |
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
-
2020
- 2020-04-01 CN CN202010248129.XA patent/CN111253346A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| WO2015101916A1 (en) * | 2013-12-30 | 2015-07-09 | Mylan Laboratories Ltd. | Process for the preparation of empagliflozin |
| US20160318965A1 (en) * | 2013-12-30 | 2016-11-03 | Mylan Laboratories Ltd. | Process for the Preparation of Empagliflozin |
| 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 |
| CN107163033A (en) * | 2017-06-15 | 2017-09-15 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method net high-purity Yi Palie |
| CN108675976A (en) * | 2018-05-14 | 2018-10-19 | 浙江宏元药业股份有限公司 | A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application |
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
Non-Patent Citations (2)
| Title |
|---|
| XIAO-JUN WANG ET AL.: "Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3-Promoted Silane Reduction of a β-Glycopyranoside", 《ORG. LETT.》 * |
| 孙履厚主编: "《精细化工新材料与技术 第一版》", 30 April 1998, 北京：中国石化出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113666892A (en) * | 2021-09-23 | 2021-11-19 | 浙江宏元药业股份有限公司 | Novel crystal form of empagliflozin intermediate and preparation method thereof |
| CN113666892B (en) * | 2021-09-23 | 2023-08-15 | 浙江宏元药业股份有限公司 | New crystal form of englitz intermediate and preparation method thereof |
| CN114773373A (en) * | 2022-04-08 | 2022-07-22 | 浙江普洛家园药业有限公司 | Preparation method of engagliflozin key intermediate and engagliflozin impurity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN111253346A (en) | Synthetic method for preparing empagliflozin intermediate | |
| CN111848365A (en) | Method for synthesizing cannabidiol | |
| CN106188062A (en) | Replace the preparation method of Buddhist nun according to Shandong, replace intermediate and the preparation method of intermediate of Buddhist nun according to Shandong | |
| CN110950765A (en) | Preparation method of terbutaline sulfate | |
| CN103420855B (en) | Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof | |
| CN112661736A (en) | Synthetic method of tylosin intermediate | |
| CN107089967A (en) | A kind of preparation method of R lipoic acids cholinester halide | |
| CN112920053B (en) | Preparation method of chiral alpha-methyl aromatic ethylamine | |
| CN110878079A (en) | Preparation method of high-purity eliagliptat | |
| CN107936045A (en) | A kind of preparation method of high-purity Flurbiprofen known impurities | |
| CN113861062A (en) | Synthesis method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate | |
| CN106749157A (en) | A kind of step of use DDB one prepares the new method of bicyclic alcohols | |
| CN105884687A (en) | Preparation method of 5-benzyl benzydamine | |
| CN115572231B (en) | Synthesis method of salt of bicyclo [1.1.1] pentane-1, 3-diamine | |
| CN113372274B (en) | Preparation method of ivabradine | |
| CN117567410A (en) | Preparation method of amiodarone hydrochloride for regulating heart rhythm | |
| CN115368234B (en) | Synthetic method of cable Ma Lutai side chain and intermediate thereof | |
| CN115504862B (en) | Preparation method of cannabigerol | |
| CN114907315B (en) | Synthesis method of Selitretinib intermediate | |
| CN118530144A (en) | Paen Jia preparation method of beach | |
| CN106083793B (en) | A kind of preparation method of 7 methoxy flavone | |
| CN117945858A (en) | Synthesis method of cannabidiol, intermediate and preparation method thereof | |
| CN116535326A (en) | Preparation method of pregabalin impurity | |
| CN115894435A (en) | Synthesis method of 1- (benzo [ b ] thiophene-4-yl) piperazine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200609 |