CN104059041B - 抗糖尿病药物达格列净中间体的制备方法 - Google Patents
抗糖尿病药物达格列净中间体的制备方法 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 15
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 239000003472 antidiabetic agent Substances 0.000 title abstract description 6
- 230000003178 anti-diabetic effect Effects 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 21
- -1 alkyl Grignard reagent Chemical class 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000003426 co-catalyst Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 8
- 239000010941 cobalt Substances 0.000 claims description 8
- 229910017052 cobalt Inorganic materials 0.000 claims description 8
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 8
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 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
- 229940079593 drug Drugs 0.000 claims description 4
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 2
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- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 150000004880 oxines Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 description 1
- 229910021584 Cobalt(II) iodide Inorganic materials 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- WDCNLMFEFWDYAV-UHFFFAOYSA-M [Mg].C(CCC)[Mg]Cl Chemical compound [Mg].C(CCC)[Mg]Cl WDCNLMFEFWDYAV-UHFFFAOYSA-M 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001869 cobalt compounds Chemical class 0.000 description 1
- AVWLPUQJODERGA-UHFFFAOYSA-L cobalt(2+);diiodide Chemical compound [Co+2].[I-].[I-] AVWLPUQJODERGA-UHFFFAOYSA-L 0.000 description 1
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开一种抗糖尿病药物达格列净中间体的制备方法,以式II所示的羟基保护的ALPHA‑D‑溴代吡喃葡萄糖为起始原料,与式III所示化合物和烷基格氏试剂发生交换反应制备的格氏试剂,在钴催化剂和配体存在下进行反应,即制得式I所示的达格列净高级中间体。本发明所需原料及试剂价格相对便宜,操作简单,成本低廉,操作简捷安全,收率良好,同时环境污染小,有很好的经济效应,适宜工业生产。
Description
技术领域
本发明涉及一种抗糖尿病药物达格列净中间体的制备方法,特别涉及一种如式I所示的抗II型糖尿病药物达格列净高级中间体的新合成方法。
技术背景
降糖药达格列净(Dapagliflozin)是由百时美施贵宝和阿斯利康公司联合开发的一种口服、每日一次的钠依赖性葡萄糖蛋白(SGLT)抑制剂。其作用机制是阻断葡萄糖在肾脏的重吸收、从而将体内过多的葡萄糖经由尿液排出,达到降低血糖的同时可以进一步减轻患者的体重。
达格列净高级中间体,其结构如下式I所示:
其中G为苄基、乙酰基,或特戊酰基。
现有技术中关于该式I中间体的合成方法主要有以下几种:
1)原研厂家百时美施贵宝公司分别在专利CN101628905A和Journal ofMedicinal Chemistry,2008,vol.51,1145-1149报道了以羟基保护的D-葡萄糖内酯为起始原料,经过加成、脱羟基和上保护等步骤得到中间体I,反应路线如下:
该路线步骤较长,需要三步才可得到该中间体。
2)Lemaire等人报道了由2,3,4,6-O-四特戊酰基-ALPHA-D-溴代吡喃葡萄糖为起始原料,经过一步偶联制得中间I的方法(Organic Letters,2012,vol.14,1480-1483),反应路线如下:
该路线相对于原研路线,缩短了步骤。但是使用的锌试剂和锂试剂均为等当量用量,造成反应体系废物多,不利于产业化生产。
发明内容
本发明所要解决的技术问题在于提供一种抗糖尿病药物达格列净中间体的制备方法,特别是提供一种简便经济的制备式I所示的抗II型糖尿病药物达格列净高级中间体的新方法。本发明所需原料及试剂价格相对便宜,操作简单,成本低廉,操作简捷安全,收率良好,同时环境污染小,有很好的经济效应,适宜工业生产。
所述的制备式I所示的抗II型糖尿病药物达格列净高级中间体的新方法,包括以下步骤:以式II所示的羟基保护的ALPHA-D-溴代吡喃葡萄糖为起始原料,与式III所示化合物和烷基格氏试剂发生交换反应制备的格氏试剂,在钴催化剂和配体存在下进行反应,即制得式I所示的达格列净高级中间体。反应式如下:
其中G为苄基,乙酰基,或特戊酰基,X为卤素,优选为溴或碘。
所述式III是由4-取代-1-氯-2-(4-乙氧苄基)苯与其它烷基格氏试剂如异丙基氯化镁、或正丁基氯化镁发生交换反应而制得的格氏试剂。
所述钴催化剂选自:1)有机钴化合物如酰丙酮钴(三乙酰丙酮钴);或2)卤化钴如氯化钴(二氯化钴)、溴化钴、碘化钴等。钴催化剂的用量为式II用量的1wt%~50wt%,优选为3wt%~10wt%。
所述配体为二胺类有机物,如:四甲基乙二胺,四甲基环己二胺,四甲基1,2-二苯基乙二胺等。配体的用量为式II用量的1wt%~50wt%,优选为3wt%~20wt%。
反应溶剂为醚类溶剂,如四氢呋喃、2-甲基四氢呋喃、乙醚、苯甲醚,或甲基叔丁基醚等。
反应温度为-20℃~60℃,优选0℃~30℃。
具体实施方式
以下实施例举例说明本发明,但并非限制本发明。
实例1(2R,3R,4R,5S,6S)-2-(乙酰甲基)-6-(4-氯-3-(4-乙氧苄基)苯基)四氢-2H-吡喃-3,4,5-三乙酰酯(Ia)的合成
方法1):50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-(乙酰氧甲基)-6-溴四氢-2H-吡喃-3,4,5-三乙酰酯(IIa,4.1g,10mmol)、四甲基乙二胺(5wt%)、三乙酰丙酮钴(5wt%)和20mL四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中制得的格氏试剂(IIIa),约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=3/1),得目标产品(4.0g,收率75%)。
MS(ESI)577.2(M+H+,100%)
方法2):50mL三口瓶中加入4-碘-1-氯-2-(4-乙氧苄基)苯(5.6g,15mmol)和2-甲基四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-(乙酰氧甲基)-6-溴四氢-2H-吡喃-3,4,5-三乙酰酯(IIa,4.1g,10mmol),四甲基乙二胺(5wt%),三乙酰丙酮钴(5wt%)和20mL 2-甲基四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中制得的格氏试剂,约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=3/1),得目标产品(4.2g,收率78%)。
MS(ESI)577.2(M+H+,100%)
方法3)50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加正丁基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-(乙酰氧甲基)-6-溴四氢-2H-吡喃-3,4,5-三乙酰酯(IIa,4.1g,10mmol),四甲基乙二胺(5wt%),三乙酰丙酮钴(5wt%)和20mL 2-甲基四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中的格氏试剂,约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=3/1),得目标产品(3.2g,收率60%)。
MS(ESI)577.2(M+H+,100%)
方法4)50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-(乙酰氧甲基)-6-溴四氢-2H-吡喃-3,4,5-三乙酰酯(IIa,4.1g,10mmol),四甲基乙二胺(10wt%),二氯化钴(10wt%)和20mL 2-甲基四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中的格氏试剂,约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=3/1),即得目标产品(4.5g,收率84%)。
MS(ESI)577.2(M+H+,100%)
方法5)50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-(乙酰氧甲基)-6-溴四氢-2H-吡喃-3,4,5-三乙酰酯(IIa,4.1g,10mmol),四甲基环己二胺(10wt%),二氯化钴(10wt%)和20mL 2-甲基四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中的格氏试剂,约30min滴加完毕,体系回温至30~35℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=3/1),即得目标产品(4.2g,收率78%)。
MS(ESI)577.2(M+H+,100%)
实例2(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧苄基)苯基)-6-(特戊酰氧甲基)四氢-2H-吡喃-3,4,5-三特戊酰酯(Ib)的合成
50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-2-溴-6-(特戊酰氧甲基)四氢-2H-吡喃-3,4,5-三特戊酰酯(IIb,5.8g,10mmol),四甲基乙二胺(5wt%),三乙酰丙酮钴(5wt%)和20mL四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中的格氏试剂,约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=6/1),即得目标产品(5.4g,收率72%)。
MS(ESI)745.4(M+H+,100%)
实例3(2R,3R,4R,5S,6S)-3,4,5-三苄氧基-2-(苄氧甲基)-6-(4-氯-3-(4-乙氧苄基)苯基)四氢-2H-吡喃(Ic)的合成
50mL三口瓶中加入4-溴-1-氯-2-(4-乙氧苄基)苯(4.9g,15mmol)和四氢呋喃20mL,搅拌降温至-5~0℃,缓慢滴加异丙基氯化镁格氏试剂(8mL,2mol/L),体系在0℃保温搅拌2h。在另一100mL三口瓶中,加入(2R,3R,4S,5R,6R)-3,4,5-三苄氧基-2-(苄氧甲基)-6-溴四氢-2H-吡喃(IIc,6.0g,10mmol),四甲基乙二胺(5wt%),三乙酰丙酮钴(5wt%)和20mL四氢呋喃,体系降温至0℃。缓慢滴加前面50mL瓶中的格氏试剂,约30min滴加完毕,体系回温至25~30℃,保温搅拌2h,用1N盐酸水溶液淬灭体系,有机相用乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析(PE/EA=9/1),即得目标产品(6.0g,收率78%)。
MS(ESI)769.3(M+H+,100%)
Claims (3)
1.一种制备如式I所示的抗II型糖尿病药物达格列净高级中间体的方法,其特征在于,包括以下步骤:以式II所示的羟基保护的ALPHA-D-溴代吡喃葡萄糖为起始原料,与式III所示化合物和烷基格氏试剂发生交换反应制备的格氏试剂,在钴催化剂和配体存在下进行反应,反应温度为-20℃~60℃,即制得式I所示的达格列净高级中间体,
其中,式II、式III和式I分别如下:
其中,G为苄基、乙酰基,或特戊酰基,X为溴或碘;
其中,所述钴催化剂选自:三乙酰丙酮钴或氯化钴,其用量为式II用量的3wt%~10wt%;所述配体为二胺类有机物,选自:四甲基乙二胺或四甲基环己二胺;所述配体的用量为式II用量的3wt%~20wt%。
2.根据权利要求1所述的方法,其特征在于,所述烷基格氏试剂为异丙基氯化镁或正丁基氯化镁。
3.根据权利要求1所述的方法,其特征在于,反应溶剂选自:四氢呋喃、2-甲基四氢呋喃、乙醚、苯甲醚,或甲基叔丁基醚。
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