CN108976182A - 一种制备达格列净五元环杂质的方法 - Google Patents
一种制备达格列净五元环杂质的方法 Download PDFInfo
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- membered ring
- tetrahydrofuran
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- dapagliflozin
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 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 14
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 14
- 239000012535 impurity Substances 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- MEMUCXUKCBNISQ-UHFFFAOYSA-N acetonitrile;trifluoroborane Chemical compound CC#N.FB(F)F MEMUCXUKCBNISQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 0 CO[C@@](C1O*)(c(cc2)cc(Cc3ccc(*C4=CCC4)cc3)c2Cl)O[C@](CO)C[C@]1O Chemical compound CO[C@@](C1O*)(c(cc2)cc(Cc3ccc(*C4=CCC4)cc3)c2Cl)O[C@](CO)C[C@]1O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- OPGQKSHKFCOBGF-UHFFFAOYSA-N methanesulfonic acid;methanol Chemical compound OC.CS(O)(=O)=O OPGQKSHKFCOBGF-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种制备达格列净五元环杂质的方法。所述方法通过下面的路线制备,该方法操作简捷安全,收率良好,且产品纯度高。
Description
技术领域
本发明涉及一种制备达格列净五元环杂质的方法。
技术背景
由百时美施贵宝和阿斯利康联合研发的达格列净于2012.11.12首次在欧洲上市,2013.01.08在美国上市,以下文献报道了达格列净的合成路线:
(1)CN 1407990报道的合成路线如下:溴代物通过和葡糖糖形成羟基中间体,还原先除去羟基,然后脱苄基得到达格列净。
(2)CN 102627676报道的合成路线如下:溴代物通过和葡糖糖反应形成羟基中间体,然后和甲醇甲磺酸得到甲氧基中间体化合物,最后通过还原得到达格列净
这两条路线最后都会经过还原步骤得到达格列净,在还原过程中会产生副产物即达格列净五元环杂质。合成五元环杂质,对于达格列净原料药的研究具有重要意义。
发明内容
本发明涉及一种制备达格列净五元环杂质的方法,概括如下:将化合物1溶解在溶剂中,加入水、路易斯酸和还原剂,反应得到化合物2;
在该制备方法中,反应溶剂选自甲苯、四氢呋喃、二氯甲烷、乙腈、甲基叔丁基醚、异丙醇、乙醇中的一种或几种,体系中加入1~4当量的水,反应温度在0~60度,路易斯酸选自三氯化铝、氯化铁、氯化锌、三氟化硼四氢呋喃、三氟化硼乙醚、三氟化硼乙腈,还原剂选自三乙基硅烷、三异丙基硅烷,后处理过程中采用饱和氯化铵水溶液淬灭反应体系,然后通过柱层析得到所需五元环杂质。
此发明所用化合物1为合成达格列净的中间体,原料易得,同时所用试剂都很常见,合成成本低,且操作简单,得到的产品纯度高。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。
实施例1:
将30mL甲苯和30mL四氢呋喃投入反应瓶中,加入10g(22.8mmol)化合物1、1.23g水(68.4mmol,3eq)、5.42g三异丙基硅烷(34.2mmol,1.5eq)和4.56g三氯化铝(34.2mmol,1.5eq),投料完毕后将反应体系升温至50度,并保温反应8h。反应结束后,体系降至室温,加入30mL饱和碳酸氢钠淬灭反应体系,分层得到有机相,有机相用饱和食盐水洗一次后浓缩除去有机溶剂,所得固油混合物通过柱层析纯化,共得到8.4g杂质2,收率90%,MS(ESI)m/z409.1([M+H]+)。
实施列2:
将30mL四氢呋喃投入反应瓶中,加入10g(22.8mmol)化合物1、1.23g水(68.4mmol,3eq)、3.98g三异丙基硅烷(34.2mmol,1.5eq)和4.75g三氟化硼四氢呋喃(34.2mmol,1.5eq),投料完毕后将反应体系升温至50度,并保温反应8h。反应结束后,体系降至室温,加入30mL饱和碳酸氢钠淬灭反应体系,加入30mL乙酸乙酯,搅拌30分钟,分层得到有机相,有机相用饱和食盐水洗一次后浓缩除去有机溶剂,所得固油混合物通过柱层析纯化,共得到8.6g杂质2,收率92%,MS(ESI)m/z 409.1([M+H]+)。
Claims (7)
1.一种制备达格列净五元环杂质(如结构式2所示)的方法,所述方法包括以下步骤:将化合物1溶解在溶剂中,加入水、路易斯酸和还原剂,反应得到化合物2;
。
2.根据权利要求1所述的方法,其特征在于溶剂选自甲苯、四氢呋喃、二氯甲烷、乙腈、甲基叔丁基醚、异丙醇、乙醇中的一种或几种,进一步优选甲苯、四氢呋喃为溶剂。
3.根据权利要求1~2所述方法,其特征在于反应过程中需要加入水,水的当量数为1~4当量,进一步优选2~3eq。
4.根据权利要求3所述方法,其特征在于反应温度为0~60度,优选40~60度。
5.根据权利要求4所述方法,其特征在于路易斯酸选自三氯化铝、氯化铁、氯化锌、三氟化硼四氢呋喃、三氟化硼乙醚、三氟化硼乙腈。
6.根据权利要求5所述方法,其特征在于还原剂为三乙基硅烷、三异丙基硅烷。
7.根据权利要求6所述方法,其特征在于后处理过程中采用饱和氯化铵水溶液淬灭反应体系,然后通过柱层析得到所需五元环杂质。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113735921A (zh) * | 2021-06-25 | 2021-12-03 | 北京惠之衡生物科技有限公司 | 一种c-糖苷类衍生物的杂质的合成方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102115468A (zh) * | 2009-12-31 | 2011-07-06 | 上海特化医药科技有限公司 | 一种2,5-二取代噻吩化合物的合成方法 |
CN106279072A (zh) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技(武汉)有限公司 | 化合物及其制备方法及用途 |
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CN102115468A (zh) * | 2009-12-31 | 2011-07-06 | 上海特化医药科技有限公司 | 一种2,5-二取代噻吩化合物的合成方法 |
CN106279072A (zh) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技(武汉)有限公司 | 化合物及其制备方法及用途 |
Non-Patent Citations (1)
Title |
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XIAO-JUN WANG等: "Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3-Promoted Silane Reduction of a β-Glycopyranoside.", 《ORG. LETT.》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113735921A (zh) * | 2021-06-25 | 2021-12-03 | 北京惠之衡生物科技有限公司 | 一种c-糖苷类衍生物的杂质的合成方法 |
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