CN109485666A - 一种烯基硼酸频哪醇酯的制备方法 - Google Patents
一种烯基硼酸频哪醇酯的制备方法 Download PDFInfo
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- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 alkenyl magnesium chloride Chemical compound 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims abstract description 9
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims abstract description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract description 5
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- WULZFOSYFJWKOH-UHFFFAOYSA-N B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O Chemical compound B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O WULZFOSYFJWKOH-UHFFFAOYSA-N 0.000 claims abstract 4
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 6
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- RQCAAFRALKAXRR-UHFFFAOYSA-N 1-ethyl-3,6-dihydro-2h-pyridine Chemical compound CCN1CCC=CC1 RQCAAFRALKAXRR-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 4
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 2
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- 229950004288 tosilate Drugs 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- AUFIRGPROMANKW-UHFFFAOYSA-N 1-methyl-3,6-dihydro-2h-pyridine Chemical compound CN1CCC=CC1 AUFIRGPROMANKW-UHFFFAOYSA-N 0.000 claims 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 claims 1
- YWKYQRWNOXUYJK-UHFFFAOYSA-N benzyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1CC=CCN1C(=O)OCC1=CC=CC=C1 YWKYQRWNOXUYJK-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 claims 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 claims 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 6
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- 238000000034 method Methods 0.000 description 8
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- 238000002156 mixing Methods 0.000 description 3
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- OTJPHTMEBBTWAP-UHFFFAOYSA-N 2,3-dimethylbutane-2,3-diol;methoxyboronic acid Chemical compound COB(O)O.CC(C)(O)C(C)(C)O OTJPHTMEBBTWAP-UHFFFAOYSA-N 0.000 description 2
- 238000006882 Shapiro reaction Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
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- 238000010025 steaming Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BDVKAMAALQXGLM-UHFFFAOYSA-N 1-ethylpiperidin-4-one Chemical class CCN1CCC(=O)CC1 BDVKAMAALQXGLM-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DAJLHNABGVYSOO-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical compound OB(O)O.CC(C)(O)C(C)(C)O DAJLHNABGVYSOO-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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Classifications
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- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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Abstract
本发明提供一种烯基硼酸频哪醇酯的通用制备方法,以脂肪酮为原料,首先与对甲苯磺酰肼反应生成对甲苯磺酰腙,腙再与格氏试剂反应生成中间体烯基氯化镁,烯基氯化镁再与甲氧基硼酸频哪醇酯(异丙氧基硼酸频哪醇酯)反应制备烯基硼酸频哪醇酯。该合成路线反应条件温和,收率高,通用性好。
Description
技术领域
本发明涉及一种烯基硼酸频哪醇酯的通用制备方法,属于有机合成技术领域。
背景技术
烯基硼酸频哪醇酯化合物广泛应用于抗癌、抗HIV药物的合成,现有的制备方法主要有如下几种:
路线一:首先由脂肪酮制备烯基锂化合物,烯基锂再与烷氧基硼酸频哪醇酯反应生成烯基硼酸频哪醇酯,如:
该合成路线收率普遍不高,单质锂太活泼,同时五氯化磷毒性较大,吸水产生大量的刺激性酸气,此法工业使用过程中存在较大的安全隐患。
路线二:首先由脂肪酮制备烯基锂化合物,烯基锂再与硼酸酯反应制备烯基硼酸频哪醇酯
该路线收率偏低,过程较多,操作繁琐,成本上优势不大;同时五氯化磷存储和使用也存在较大的风险,操作环境比较恶劣。
路线三:首先由脂肪酮制备二溴化合物,脱溴后成烯基溴,烯基溴再与二硼烷频哪酯反应制备烯基硼酸频哪醇酯
该方法过程较长,原子利用率低,DBU及Pd(dppf)Cl2价格高昂,此路线不经济,成本较高 路线四 :以脂肪酮为原料,先与对甲苯磺酰肼反应制备对甲苯磺酰腙,腙与硼酸频哪醇酯在正丁基锂存在的条件下,发生Shapiro反应制备目标产物
该路线虽然流程短,但采用高度易燃正丁基锂,生产环节存在很大的安全隐患。
发明内容
针对以上几种常见制备路线的不总,本发明提供一种改进的Shapiro反应制备方法,收率高,选择性好,条件温和,原料低廉,对烯基硼酸频哪醇酯的制备具有通用性,适合工业化放大生产。如:
本发明的主要特征为:采用脂肪酮为原料,先与对甲苯磺酰肼反应制备对甲苯磺酰腙,腙与格氏试剂反应生成中间体烯基氯化镁,烯基氯化镁不经分离,直接加入硼酸频哪醇酯反应制备目标产物烯基硼酸频哪醇酯。
具体实施实例:
【实施例1】环己烯-1-硼酸频哪醇酯的制备
将环己酮(20g,0.2mol)、吡啶对甲苯磺酸盐(5g,0.02mol)、对甲苯磺酰肼(38g,0.2mol)、乙腈(200mL)混合后,升温至回流,反应结束后,减压蒸出乙腈,加入异丙醇重结晶后得磺酰腙化合物49g,收率90%;
将磺酰腙化合物(49g,0.18mol)、异丙基氯化镁溶液(370mL,1.0M)、四甲基乙二胺(23g,0.2mol)混合,在40℃条件下反应3h.反应完毕,滴加甲基硼酸频哪醇酯(26.5g,0.19mol),反应2h,然后升温至回流反应1h。反应完毕,蒸出溶剂后,继续在100℃左右蒸出产品环己烯-1-硼酸频哪醇酯,得27.5g,收率89%。
【实施例2】1-乙基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯的制备
将N-乙基-4-哌啶酮(25g,0.2mol)、吡啶对甲苯磺酸盐(5g, 0.02mol)、对甲苯磺酰肼(40g, 0.21mol)、乙醇(250mL)混合后,升温至回流,反应结束后,蒸出溶剂,加入异丙醇重结晶后的磺酰腙化合物50g,收率86%;
将化合物腙(50g,0.17mol)、异丙基氯化镁溶液(430mL,1.0M)、四甲基乙二胺(22g,0.19mol)混合,在回流条件下反应3h.反应完毕,滴加甲基硼酸频哪醇酯;(24g,0.17mol),反应2h,然后升温至回流反应1h。反应完毕,蒸出溶剂后,继续蒸出产品1-乙基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯,得25.5g,收率67.5%。
Claims (7)
1.本发明涉及一种烯基硼酸频哪醇酯的通用制备方法,其特征在于以脂肪酮为原料,通过以下步骤合成目标产物:
脂肪酮在一定溶剂中,以对甲苯磺酸盐(PPTS)为脱水催化剂,在一定反应温度下,与对甲苯磺酰肼反应生成对甲苯磺酰腙
在一定的溶剂中,在四甲基乙二胺(TMEDA)存在的条件下,对甲苯磺酰腙与异丙基氯化镁反应生成中间体烯基氯化镁,之后加入甲氧基硼酸频哪醇酯(异丙氧基硼酸频哪醇酯),一锅制备烯基硼酸频哪醇酯。
2.根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于所述烯基硼酸频哪醇酯特别是针对:环己烯-1-硼酸频哪醇酯(式1);环戊烯-1-硼酸频哪醇酯(式2)1-乙基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯(式3);1-甲基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯(式4);N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(式5);N-Bn-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(式6);N-CBZ--1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(式7);N-Bz-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(式8);N-Fmoc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(式9);3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(式10);以及其他烯基硼酸频哪醇酯化合物(式11~19)。
3. 根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于步骤1)反应溶剂为甲醇、乙醇、乙腈、***、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙二醇二甲醚、1,2-二氯乙烷、二氯甲烷、三氯甲烷、氯苯中的任意一种,并不仅局限于此;反应温度为0~100℃。
4.根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于步骤1)中
脂肪酮、对甲苯磺酰肼、对甲苯磺酸盐的摩尔比为1:1.0~1.5:0.05~0.2。
5.根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于步骤2)反应溶剂为四氢呋喃、甲苯、二甲苯、乙二醇二甲醚、乙二醇甲醚、甲基叔丁基醚、甲基四氢呋喃等,抑或是其中两种及两种以上混合溶剂;所述硼酸频哪醇酯为甲氧基硼酸频哪醇酯或是异丙氧基硼酸频哪醇酯。
6.根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于步骤2)对甲苯磺酰腙与四甲基乙二胺(TMEDA)摩尔比为1:1.0~2.5;所述反应温度为-20~80℃。
7.根据权利要求1所述一种烯基硼酸频哪醇酯的通用制备方法,其特征在于步骤2)对甲苯磺酰腙、异丙基氯化镁、甲氧基硼酸频哪醇酯(异丙氧基硼酸频哪醇酯)的摩尔比为1:2.0~2.5:1~1.1 。
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