CN116462670A - 一锅法制备恩格列净的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 23
- CSQCYSDEAYXXTN-UHFFFAOYSA-N 4-[(5-bromo-2-chlorophenyl)methyl]phenol Chemical compound C1=CC(O)=CC=C1CC1=CC(Br)=CC=C1Cl CSQCYSDEAYXXTN-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 238000005935 nucleophilic addition reaction Methods 0.000 claims abstract description 10
- 230000011987 methylation Effects 0.000 claims abstract description 8
- 238000007069 methylation reaction Methods 0.000 claims abstract description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 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 16
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 238000003747 Grignard reaction Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001012 protector Effects 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 229910000077 silane Inorganic materials 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000005119 centrifugation Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010981 drying operation Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229950002375 englitazone Drugs 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- -1 glucose lactone Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- ISYOFZCEMBXHOL-UHFFFAOYSA-M [Li].CC(C)[Mg]Cl Chemical compound [Li].CC(C)[Mg]Cl ISYOFZCEMBXHOL-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MXOSTENCGSDMRE-UHFFFAOYSA-N butyl-chloro-dimethylsilane Chemical group CCCC[Si](C)(C)Cl MXOSTENCGSDMRE-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 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 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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- 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
- C07B2200/07—Optical isomers
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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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- Biotechnology (AREA)
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Abstract
本发明属于药物合成技术领域,具体涉及一种一锅法制备恩格列净的方法。该制备方法为:以4‑(5‑溴‑2‑氯苄基)苯酚为起始原料,在格氏试剂作用下与糖发生亲核加成;再加入氯化氢甲醇溶液发生甲醚化;接着与(R)‑3‑对甲苯磺酸四氢呋喃酯发生亲核取代反应,最后加入Et3SiH/AlCl3发生还原反应,制得恩格利净粗品。本发明提供的“一锅法”制备恩格列净粗品的方法,反应过程不用拿出中间体,避免了离心,干燥操作,大大缩短生产周期。该制备方法操作简便,后处理易操作,溶剂易回收;并且大大地提高了产能,精制后成品纯度在99.5%以上,产品总收率可达到40%,杂质易于控制,适合工业化生产。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种一锅法制备恩格列净的方法。
背景技术
恩格列净(Empagliflozin)是一种钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂,可有效阻断肾脏对葡萄糖的重吸收,增加葡萄糖排泄,降低血糖水平。恩格列净结合饮食及运动用于2型糖尿病成人患者的治疗,可以改善血糖控制。恩格列净的化学名称为(1S)-1,5-脱水-1-C-(4-氯-3-((4-(((3S)-四氢-3-呋喃基)氧基)苯基)甲基)苯基)-D-葡萄糖醇,相对分子质量为450.91,分子式为C23H27ClO7,结构式如式Ⅲ所示。
目前,恩格列净的合成技术已相对成熟,但是现有的恩格列净的合成工艺大多存在工艺路线长、收率低、难以工业化生产等缺陷。例如,恩格列净的原研专利(US7579449B2、US7713938B2、US7745414B2、US7776830B2),以2-氯-5-溴苯甲酸为起始原料,经酰氯化、傅克酰基化、羰基还原、酸性水解,得到苯酚衍生物,苯酚衍生物中酚羟基用叔丁基二甲基氯硅烷(TBDMSCl)保护后,在正丁基锂(n-BuLi)作用下,与糖发生亲核加成,接着甲醚化,用Et3SiH/BF3·Et2O体系还原消除异头碳上的羟基,再与(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,得到最终产品恩格列净。该工艺路线较长,总收率仅为12%;简略合成路线如下:
申请号为CN201710070415.X、CN201910535608.7等发明专利,选择以(3S)-3-[4-[(2-卤-5-碘苯基)甲基]苯氧基]四氢呋喃为起始原料,在正丁基锂作用下,与糖发生亲核加成,接着甲醚化,用Et3SiH/BF3·Et2O体系还原消除异头碳上的羟基,得到最终产品恩格列净。该工艺路线较原研工艺路线缩短,收率提高,但关键物料(3S)-3-[4-[(2-卤-5-碘苯基)甲基]苯氧基]四氢呋喃较难获得,不适合工业化生产;简略合成路线如下:
因此,亟需对恩格列净的现有制备工艺进行优化,探索出一种新的制备方法,以克服现有技术缺陷。
发明内容
有鉴于此,本发明的目的之一在于提供一种一锅法制备恩格列净的方法,直接以4-(5-溴-2-氯苄基)苯酚为原料,在一个反应容器中连续发生亲核加成反应、甲醚化、亲核取代反应和还原反应,制得恩格列净粗品,反应过程中无需拿出中间体,适用于恩格列净的规模化生产。
为实现上述目的,本发明采用以下技术方案:
一锅法制备恩格列净的方法,包括以下步骤:
S1:以4-(5-溴-2-氯苄基)苯酚和葡萄糖内酯为原料,加入溶剂1和催化剂,反应获得羟基保护物;
S2:S1所得羟基保护物中加入格氏试剂发生亲核加成反应,甲醚化获得化合物I溶液,
S3:S2所得化合物I溶液在碱性条件下加入(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,获得化合物Ⅱ溶液;
S4:向S3所得化合物Ⅱ溶液中加入Et3SiH/AlCl3发生还原反应,获得恩格利净粗品;
所述化合物I、化合物Ⅱ、恩格利净和羟基保护物的结构式依次如式I、式Ⅱ、式Ⅲ和式Ⅳ所示;所述恩格列净粗品的制备发生在在一个反应容器中,反应过程中无需拿出中间体;
本发明以4-(5-溴-2-氯苄基)苯酚为起始原料,在格氏试剂作用下,与糖发生亲核加成,接着甲醚化,再与(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,最后利用Et3SiH/AlCl3体系还原消除异头碳上的羟基,反应过程不用拿出中间体,避免了离心,干燥操作,减少离心、干燥设备,大大缩短生产周期,产品总收率由原研专利的12%提高至40%。
进一步,S1中,所述溶剂1为二氯甲烷、三氯甲烷、二氯乙烷中的任一种或多种。
作为优选,所述溶剂1为二氯甲烷。二氯甲烷作为溶剂,对产品质量和收率均有提高作用,且价格便宜易得。
进一步,S1中,所述4-(5-溴-2-氯苄基)苯酚、所述葡萄糖内酯和所述催化剂的摩尔比为1:1-2:0.01-0.5;所述催化剂为碘、碘化钠、碘化钾中的任一种或多种。
作为优选,所述催化剂为碘。碘作为催化剂,在溶剂中的溶解性最好,明显缩短了反应时间。
进一步,S2中,所述格式试剂为正丁基锂溶液、异丙基氯化镁、叔丁基锂中的任一种或多种;所述4-(5-溴-2-氯苄基)苯酚和所述格式试剂的摩尔比为1:1.0-1.5。
作为优选,所述格式试剂为异丙基氯化镁。
作为优选,所述4-(5-溴-2-氯苄基)苯酚和格式试剂的摩尔比为1:1.1。
进一步,所述亲核加成反应的反应温度-20℃~-50℃。
进一步,S2中,格氏交换反应溶剂为无水乙醚、四氢呋喃中的任一种或多种。
作为优选,所述格氏交换反应溶剂为四氢呋喃。
进一步,S3中,碱为甲醇钠、乙醇钠、叔丁醇钾中的任一种或多种;所述4-(5-溴-2-氯苄基)苯酚和碱的摩尔比为1:1.5-2.0。
作为优选,所述碱为叔丁醇钾。
作为优选,所述4-(5-溴-2-氯苄基)苯酚和碱的摩尔比为1:1.6。
进一步,S4中,所述化合物Ⅱ溶液在溶剂2和还原剂的作用下与Et3SiH/AlCl3发生反应,所述溶剂2为二氯甲烷、三氯甲烷、乙腈中的任一种或多种;所述还原剂为硼氢化钠、三乙基硅烷/三氯化铝体系、三乙基硅烷/三氟化硼体系中的任一种或多种。
作为优选,所述还原剂为三乙基硅烷/三氟化硼体系,更优选为三乙基硅烷和三氟化硼乙醚。
进一步,将所述恩格利净粗品高温溶解于溶剂中,过滤,降温析晶、离心、干燥、粉碎,获得恩格利净成品。
更进一步,所述溶剂为乙醇、甲醇、乙醇水、甲醇水、甲苯、二甲苯中的任一种或多种。
进一步,所述恩格列净粗品在搪玻璃反应罐进行制备;在所述搪玻璃反应罐中,所述4-(5-溴-2-氯苄基)苯酚先与所述葡萄糖内酯发生亲核加成反应,甲醚化后得到所述化合物I溶液;所述化合物I溶液与所述(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,得到所述化合物Ⅱ溶液;所述化合物Ⅱ溶液继续加入所述Et3SiH/AlCl3发生还原反应,制得所述恩格利净粗品。
本发明的有益效果在于:
1.本发明提供的恩格列净的制备方法,直接以4-(5-溴-2-氯苄基)苯酚为原料,一锅法制备恩格利净粗品,反应过程中不需要拿出各中间体,减少了中间体的纯化与干燥过程,提高收率,缩短制造周期。
2.本发明的工艺单步反应溶剂单一,便于回收套用。
3.本发明的工艺设备使用少,设备要求较低,后处理简便时间短,便于规模化生产。
4.本发明的工艺制得的产品纯度、收率高,产品总收率由原研专利的12%提高至40%,产品纯度在99.5%以上,满足用药要求。
附图说明
图1为本发明的反应路线图;
图2为本发明的生产流程图。
具体实施方式
下面将结合具体的实施例对本发明的技术方案进行更进一步地清楚、完整地描述。显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部实施例。因此,基于本发明中的实施例,本领域技术人员在没有付出创造性劳动前提下所获得的其他所有实施例都属于本发明的保护范围。
实施例1.一锅法制备恩格利净粗品
在三口瓶中加入29.8g 4-(5-溴-2-氯苄基)苯酚,19.6g葡萄糖内脂,500ml二氯甲烷,2.6g碘,87.1g六甲基二硅胺烷,回流反应24-36h,降温至0-5℃,用1%硫代硫酸钠水溶液洗涤分层,浓缩二氯甲烷,得无色至淡黄色油状液体,加入300ml四氢呋喃稀释,搅拌降温至-40至-50℃,滴加32.8g异丙基氯化镁氯化锂溶液,-40℃保温搅拌1h。再升温至-10至-20℃,滴加10%氯化氢甲醇溶液25g,控温0℃以下搅拌反应6-10h。反应完毕,加入15g碳酸钠,调节PH为7-8,控温30℃以下减压浓缩,得到110g淡黄色化合物I悬浊液体,液相纯度90%。
用500ml四氢呋喃稀释110g化合物I悬浊液,控制水分0.5%以下,加入(R)-3-对甲苯磺酸四氢呋喃酯26.6g,搅拌降温至-5至0℃,滴加10%叔丁醇钾四氢呋喃溶液123g,滴加完毕升温至30-40℃保温搅拌3-5h,在减压蒸馏至恒重,得到淡黄色固体。加入300ml二氯甲烷搅拌溶解,加入100ml水*2洗涤分层两次,再用100ml饱和食盐水洗涤1次。有机相水分控制0.3%以下,得到化合物II有机相。
化合物II二氯甲烷有机相,降温至-10至0℃,加入12g三氟化硼乙醚,搅拌30min,滴加三乙基硅烷,滴加完毕,保温搅拌10min,加入200ml水淬灭反应,减压蒸馏二氯甲烷,析出固体,加入乙醇搅拌30min,过滤用乙醇洗涤滤饼,干燥,得到类白色恩格利净粗品25g,摩尔收率55%,纯度98.0%。
实施例2.一锅法制备恩格利净粗品
在三口瓶中加入29.8g 4-(5-溴-2-氯苄基)苯酚,19.6g葡萄糖内脂,500ml二氯甲烷,2.6g碘,87.1g六甲基二硅胺烷,回流反应24-36h,降温至0-5℃,用1%硫代硫酸钠水溶液洗涤分层,浓缩二氯甲烷,得无色至淡黄色油状液体,加入500ml无水乙醚稀释,搅拌降温至-60至-70℃,滴加32g 20%正丁基锂溶液,-60℃保温搅拌1h。再升温至-10至-20℃,滴加1%氯化铵水溶液100ml淬灭反应,分层浓缩乙醚,得到黄色油状物,加入200ml甲醇,降温至0-5℃,滴加10%氯化氢甲醇溶液25g,控温0℃以下搅拌反应6-10h。反应完毕,加入15g碳酸钠,调节PH为7-8,过滤,向料液中加入(R)-3-对甲苯磺酸四氢呋喃酯23g,搅拌降温至-5至0℃,滴加30%甲醇钠溶液18g,保温搅拌3-5h,减压蒸馏至恒重,得到淡黄色固体。加入300ml二氯甲烷搅拌溶解,加入100ml水*2洗涤分层两次,再用100ml饱和食盐水洗涤1次。有机相水分控制0.3%以下,得到化合物II有机相。
化合物II二氯甲烷有机相,降温至-10至0℃,加入12g三氟化硼乙醚,搅拌30min,滴加三乙基硅烷,滴加完毕,保温搅拌10min,加入200ml水淬灭反应,减压蒸馏二氯甲烷,析出固体,加入乙醇搅拌30min,过滤用乙醇洗涤滤饼,干燥,得到类白色恩格利净粗品23g,摩尔收率50.9%,纯度95.0%。
实施例3.恩格利净成品的制备
采用实施例1的方法制备恩格利净粗品,将恩格利净粗品20g加入反应瓶中,加入80g乙醇升温至70℃溶解,再降温至50℃析出固体,保温搅拌1h,再降温至10-20℃,过滤,用乙醇洗涤滤饼,干燥,得白色固体16.1g,纯度99.8%。
实施例4.恩格利净成品的制备
采用实施例1的方法制备恩格利净粗品,将恩格利净粗品20g加入反应瓶中,加入80g乙醇升温至70℃溶解,再降温至50℃析出固体,保温搅拌1h,再降温至10-20℃,滴加10g水,过滤,用乙醇洗涤滤饼,干燥,得白色固体17.5g,纯度99.0%。
实施例5.恩格利净成品的制备
采用实施例1的方法制备恩格利净粗品,将恩格利净粗品20g加入反应瓶中,加入80g95%乙醇回流溶清,再降温析出固体,保温搅拌1h,再降温至10-20℃,过滤,用95%乙醇洗涤滤饼,干燥,得白色固体18.2g,纯度99.5%。
实施例6.恩格利净成品的制备
采用实施例1的方法制备恩格利净粗品,将恩格利净粗品20g加入反应瓶中,加入80g甲苯回流溶清,再降温析出固体,保温搅拌1h,再降温至10-20℃,过滤,用甲苯洗涤滤饼,干燥,得白色固体17.9g,纯度98.8%。
Claims (10)
1.一锅法制备恩格列净的方法,其特征在于,包括以下步骤:
S1:以4-(5-溴-2-氯苄基)苯酚和葡萄糖内酯为原料,加入溶剂1和催化剂,反应获得羟基保护物;
S2:S1所得羟基保护物中加入格氏试剂发生亲核加成反应,甲醚化获得化合物I溶液,
S3:S2所得化合物I溶液在碱性条件下加入(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,获得化合物Ⅱ溶液;
S4:向S3所得化合物Ⅱ溶液中加入Et3SiH/AlCl3发生还原反应,获得恩格利净粗品;
所述化合物I、化合物Ⅱ、恩格利净和羟基保护物的结构式依次如式I、式Ⅱ、式Ⅲ和式Ⅳ所示;所述恩格列净粗品的制备发生在在一个反应容器中,反应过程中无需拿出中间体;
2.根据权利要求1所述的方法,其特征在于,S1中,所述溶剂1为二氯甲烷、三氯甲烷、二氯乙烷中的任一种或多种。
3.根据权利要求1所述的方法,其特征在于,S1中,所述4-(5-溴-2-氯苄基)苯酚、所述葡萄糖内酯和所述催化剂的摩尔比为1:1-2:0.01-0.5;所述催化剂为碘、碘化钠、碘化钾中的任一种或多种。
4.根据权利要求1所述的方法,其特征在于,S2中,所述格式试剂为正丁基锂溶液、异丙基氯化镁、叔丁基锂中的任一种或多种;所述4-(5-溴-2-氯苄基)苯酚和所述格式试剂的摩尔比为1:1.0-1.5。
5.根据权利要求1所述的方法,其特征在于,S2中,格氏交换反应溶剂为无水乙醚、四氢呋喃中的任一种或多种。
6.根据权利要求1所述的方法,其特征在于,S3中,碱为甲醇钠、乙醇钠、叔丁醇钾中的任一种或多种;所述4-(5-溴-2-氯苄基)苯酚和碱的摩尔比为1:1.5-2.0。
7.根据权利要求1所述的方法,其特征在于,S4中,所述化合物Ⅱ溶液在溶剂2和还原剂的作用下与Et3SiH/AlCl3发生反应,所述溶剂2为二氯甲烷、三氯甲烷、乙腈中的任一种或多种;所述还原剂为硼氢化钠、三乙基硅烷/三氯化铝体系、三乙基硅烷/三氟化硼体系中的任一种或多种。
8.根据权利要求1所述的方法,其特征在于,将所述恩格利净粗品高温溶解于溶剂3中,过滤,降温析晶、离心、干燥、粉碎,获得恩格利净成品。
9.根据权利要求8所述的方法,其特征在于,所述溶剂3为乙醇、甲醇、乙醇水、甲醇水、甲苯、二甲苯中的任一种或多种。
10.根据权利要求1所述的方法,其特征在于,其特征在于,所述恩格列净粗品在搪玻璃反应罐进行制备;在所述搪玻璃反应罐中,所述4-(5-溴-2-氯苄基)苯酚先与所述葡萄糖内酯发生亲核加成反应,甲醚化后得到所述化合物I溶液;所述化合物I溶液与所述(R)-3-对甲苯磺酸四氢呋喃酯发生亲核取代反应,得到所述化合物Ⅱ溶液;所述化合物Ⅱ溶液继续加入所述Et3SiH/AlCl3发生还原反应,制得所述恩格利净粗品。
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