CN114133373A - 一种合成维兰特罗中间体的前驱体的方法 - Google Patents
一种合成维兰特罗中间体的前驱体的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 239000002243 precursor Substances 0.000 title description 4
- AKLUHFHHUBIDQA-UHFFFAOYSA-N 2-[2-(6-bromohexoxy)ethoxymethyl]-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1COCCOCCCCCCBr AKLUHFHHUBIDQA-UHFFFAOYSA-N 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- NEOSFTXNNNEDMY-JTQLQIEISA-N (1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol Chemical compound [O-][N+](=O)C[C@H](O)C1=CC=C2OC(C)(C)OCC2=C1 NEOSFTXNNNEDMY-JTQLQIEISA-N 0.000 claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 30
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 20
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- 235000010288 sodium nitrite Nutrition 0.000 claims description 15
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- 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 description 4
- 238000002156 mixing Methods 0.000 claims description 4
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- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 3
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- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims 2
- 238000006842 Henry reaction Methods 0.000 abstract description 7
- -1 2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl Chemical group 0.000 abstract description 4
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- 238000006722 reduction reaction Methods 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- 239000000654 additive Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
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- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
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- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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Abstract
Description
技术领域
本发明属于有机化学合成领域,具体涉及一种合成一种合成维兰特罗中间体的前驱体的方法,即(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法。
背景技术
(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇可用作合成(5R)-5- (2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮的前驱体,而(5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮是合成维兰特罗的重要中间体,其可用作长效β2肾上腺素受体激动剂。
(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇
(5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮
目前,(5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮现行合成路线如下所示:
该路线存在诸多不足:例如,1)在第二步将酮进行手性催化还原成醇时,用了大剂量(0.3单量)的手性催化剂(R)-2-甲基-CBS-恶唑硼烷;2)该路线包含两次上保护基团跟脱保护基团的步骤(分别是三乙基硅基以及苄基),原子经济性低;3)合成路线步骤较长,总共包含7步。
综上所述,制药行业的发展迫切需要开发一个可以低成本、可产业化的工艺路线用于合成关键中间体(5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮。
发明内容
本发明开发了一条适合工业化生产制备(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的工艺路线,以其作为重要中间体,缩短并优化现阶段合成 (5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮的工艺路线,具体包括以下反应步骤:
本发明的工艺路线从原工艺中的VLO6中间体(式II化合物)出发,与亚硝酸钠在咪唑基聚离子液体(见结构式1)的催化作用下发生SN2取代反应,生成式III化合物;然后在不对称催化转移氢化条件下还原,得到(1R)-1-(2,2-二甲基 -4H-1,3-苯并二恶英-6-基)-2-硝基乙醇(式I化合物)。式I化合物随后可以通过进一步硝基还原得到VL11中间体。
与原工艺相比,本发明的工艺路线有如下几个优点:
(1)手性催化剂用量低,只需0.05当量,并且反应收率高,因此反应催化转化数高。
(2)使用转移氢化的方式还原式III化合物,适合放大生产。
(3)合成路线简单,将VL06到VL11的反应步骤从原工艺的5步缩减为3步,而且有较好的原子经济性。
(4)第二步反应的副产物是水,三废处理较为简易,有利于工业化生产。
目前(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇主要由不对称Henry反应合成。如下所示。
在文献doi:10.1016/j.tetasy.2011.08.008报道的方法中,该路线使用较为昂贵的(-)-鹰爪豆碱(5600元/克)为配体,在氯化铜(II)二水合物的催化作用下,发生不对称Henry反应合成。并且,配体跟催化剂的使用当量较大,均为0.2摩尔当量。
另一条路线中(doi:10.1016/j.tetasy.2015.01.001)使用了原位生成的醋酸铜/手性咪唑啉-4-酮衍生物为催化剂,进行不对称Henry反应合成了(1R)-1-(2,2- 二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇。该路线配体的合成较为繁杂,需要六个反应步骤制备而成。并且,该催化体系合成的产物收率较低,只有50%。
除了上述缺点,不对称Henry反应的路线使用了易爆的硝基甲烷,具有较大的安全隐患。
与利用不对称Henry反应制备(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基) -2-硝基乙醇的路线相比,本发明的合成路线所需催化剂价格较为低廉(189元/ 克),α-硝基酮还原步骤摩尔收率大于85%,具有不对称选择性高、易于生产的特点。
本发明的实施例提供一种合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,所述方法路线如下:
根据本发明的一种实施方式,例如,所述步骤S1所需的亚硝酸盐可以选择亚硝酸钠、亚硝酸钾等。优选为亚硝酸钠。亚硝酸盐用量为1.0-2.0当量,优选为1.5 当量。较低的亚硝酸钠用量会减缓反应的速率,而较大量的亚硝酸钠用量不利于放大生产。
根据本发明的一种实施方式,例如,所述步骤S2所需的添加剂为N,N-二甲基甲酰胺(DMF)、水等,优选为DMF。
根据本发明的一种实施方式,例如,所述步骤S2所需的催化剂为手性二胺/ 钌催化剂;优选的,所述手性二胺/钌催化剂选自下述中的至少一种:RuCl[(S,S)- TsDPEN](p-cymene)(cat.1),RuCl[(S,S)-TsDPEN](1,3,5-trimethyl benzene)(cat.2), RuCl[(S,S)-TsDPEN](benzene)(cat.3),RuCl[(S,S)-FsDPEN](p-cymene)(cat.4)。 (Scheme 1),优选为RuCl[(S,S)-TsDPEN](p-cymene)(cat.1)。
手性二胺/钌催化剂的结构
本发明的实施例提供一种合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,所述方法路线如下:
根据本发明的一种实施方式,例如,所述步骤S1加入亚硝酸盐和咪唑基聚离子液体催化剂;
优选的,所述亚硝酸盐包括亚硝酸钠和/或亚硝酸钾;
进一步优选的,所述亚硝酸盐为亚硝酸钠。亚硝酸钠来源更广泛,价格更低廉。
根据本发明的一种实施方式,例如,所述的亚硝酸盐用量为1.0-2.0当量,优选为1.5当量。较低的亚硝酸钠用量会减缓反应的速率,而较大量的亚硝酸钠用量不利于放大生产。
根据本发明的一种实施方式,例如,所述S1、S2的反应温度为40-70℃,优选为60℃。较低的反应温度会减缓反应的速率,而较高的反应温度会让反应的副反应增多。
根据本发明的一种实施方式,例如,所述方法包括:
S1:向反应瓶中加入水、化合物II、咪唑基聚离子液体催化剂、亚硝酸盐,升温至60℃搅拌;反应一段时间后,停止搅拌,加入有机溶剂萃取,合并所得有机相并干燥;过滤,浓缩有机相,纯化浓缩物,制得化合物III;
S2:向反应瓶中加入式III化合物,催化剂,有机溶剂,取三乙胺和甲酸搅拌混合均匀,随后加入到反应瓶中,升温至50-70℃反应,分离提纯得到化合物I;
优选的,所述步骤S1中,亚硝酸盐为亚硝酸钠;
优选的,所述步骤S1中,反应一段时间为20min以上,进一步优选20min- 30min;
优选的,所述步骤S1中,所述有机溶剂为乙醚;
优选的,所述步骤S1中,通过硅胶柱层析纯化浓缩物;
优选的,所述步骤S2中,反应在惰性气体环境下进行;
优选的,所述步骤S2中,所述分离提纯包括:向反应液加入乙酸乙酯,分离所得有机相并用无水硫酸钠干燥,过滤,真空浓缩。
根据本发明的一种实施方式,例如,所述步骤S2需加入催化剂和溶剂,所述溶剂包括N,N-二甲基甲酰胺(DMF)和/或水,优选为DMF优选DMF的原因为反应物在DMF中溶解性较好。
根据本发明的一种实施方式,例如,所述步骤S2中加入的催化剂为手性二胺 /钌催化剂;
优选的,所述手性二胺/钌催化剂选自下述中的至少一种:RuCl[(S,S)- TsDPEN](p-cymene)(cat.1),RuCl[(S,S)-TsDPEN](1,3,5-trimethyl benzene)(cat.2), RuCl[(S,S)-TsDPEN](benzene)(cat.3),RuCl[(S,S)-FsDPEN](p-cymene)(cat.4);
优选的,所述步骤S2中加入的催化剂为RuCl[(S,S)-TsDPEN](p-cymene)(cat.1)。
根据本发明的一种实施方式,例如,所述步骤S2包括:
在氮气保护的条件下向反应瓶中加入式III化合物、催化剂、溶剂;
取三乙胺和甲酸搅拌充分混合,随后加入到反应瓶中,升温至60℃反应一段时间;三乙胺与甲酸的混合物能够提供氢转移试剂。
加入乙酸乙酯,分离所得有机相并用干燥、过滤,真空浓缩得到化合物I;
优选的,所述溶剂为DMF;
优选的,所述反应一段时间为反应过夜;
优选的,所述干燥为用无水硫酸钠干燥。
根据本发明的一种实施方式,例如,所述咪唑基聚离子液体催化剂的结构式为:
结构式1:咪唑基聚离子液体催化剂的结构
本发明带来的优异技术效果包括:采用本发明合成方法合成(1R)-1-(2,2- 二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇,应用于制备(5R)-5-(2,2-二甲基- 4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮的方法中,可以缩短反应步骤,具有反应转化数高、原子经济性高、适合工业化生产等优点。与目前报道的利用不对称 Henry反应合成路线相比,本发明的合成路线所需催化剂价格较为低廉,α-硝基酮还原步骤摩尔收率大于85%,具有不对称选择性高、易于生产的特点。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例的附图作简单地介绍,显然,下面描述中的附图仅仅涉及本发明的一些实施例,而非对本发明的限制。
图1是式I化合物的核磁共振氢谱。
图2是式I化合物消旋体的超临界流体色谱(SFC)谱图。
图3是本发明实施例1 S2步骤生成的式I化合物的SFC谱图。
具体实施方式
下文将结合具体实施例对本发明的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法做更进一步的说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
实施例1
S1:SN2取代反应制得α-硝基酮类化合物III
向反应瓶中加入水、化合物II(285g)、咪唑基聚离子液体催化剂(0.1g,结构式如下)、亚硝酸钠(104g,1.5eq.),升温至60℃搅拌。反应20min后,停止搅拌。加入乙醚萃取三次,合并所得有机相并用无水硫酸钠干燥。过滤,浓缩有机相,通过硅胶柱层析纯化浓缩物,制得化合物III 176g,收率70%。
结构式1:咪唑基聚离子液体催化剂的结构
S2:催化转移氢化制得α-硝基醇类化合物I
在氮气保护的条件下向反应瓶中加入式III化合物(10g,1.0eq.),催化剂RuCl[(S,S)-TsDPEN](p-cymene)(1.25g,0.05eq.),DMF(50mL)。取三乙胺(8.7mL)和甲酸(3.8mL)搅拌3分钟,随后加入到反应瓶中,升温至60℃反应过夜。之后向反应液加入乙酸乙酯,分离所得有机相并用无水硫酸钠干燥。过滤,真空浓缩得到化合物I 8.7g,收率87%,ee值94.3%。1H NMR(600MHz, CDCl3)δ7.10(d,J=7.8 Hz,1H),6.95(s,1H),6.78(d,J=7.8Hz,1H),4.80(s, 2H),4.70(s,1H),3.64(d,J=47.2 Hz,2H),1.52(s,6H).
Claims (9)
2.根据权利要求1所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述步骤S1加入亚硝酸盐和咪唑基聚离子液体催化剂;
优选的,所述亚硝酸盐包括亚硝酸钠和/或亚硝酸钾;
进一步优选的,所述亚硝酸盐为亚硝酸钠。
3.根据权利要求2所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述的亚硝酸盐用量为1.0-2.0当量,优选为1.5当量。
4.根据权利要求3所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述S1、S2的反应温度为40-70℃,优选为60℃。
5.根据权利要求4所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述方法包括:
S1:向反应瓶中加入水、化合物II、咪唑基聚离子液体催化剂、亚硝酸盐,升温至60℃搅拌;反应一段时间后,停止搅拌,加入有机溶剂萃取,合并所得有机相并干燥;过滤,浓缩有机相,纯化浓缩物,制得化合物III;
S2:向反应瓶中加入式III化合物,催化剂,有机溶剂,取三乙胺和甲酸搅拌混合均匀,随后加入到反应瓶中,升温至50-70℃反应,分离提纯得到化合物I;
优选的,所述步骤S1中,亚硝酸盐为亚硝酸钠;
优选的,所述步骤S1中,反应一段时间为20min以上,进一步优选20min-30min;
优选的,所述步骤S1中,所述有机溶剂为乙醚;
优选的,所述步骤S1中,通过硅胶柱层析纯化浓缩物;
优选的,所述步骤S2中,反应在惰性气体环境下进行;
优选的,所述步骤S2中,所述分离提纯包括:向反应液加入乙酸乙酯,分离所得有机相并用无水硫酸钠干燥,过滤,真空浓缩。
6.根据权利要求1-5任一项所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述步骤S2中的有机溶剂包括N,N-二甲基甲酰胺(DMF)和/或水,优选为DMF。
7.根据权利要求6所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述步骤S2中加入的催化剂为手性二胺/钌催化剂;
优选的,所述手性二胺/钌催化剂选自下述至少一种:RuCl[(S,S)-TsDPEN](p-cymene)(cat.1),RuCl[(S,S)-TsDPEN](1,3,5-trimethylbenzene)(cat.2),RuCl[(S,S)-TsDPEN](benzene)(cat.3),RuCl[(S,S)-FsDPEN](p-cymene)(cat.4);
优选的,所述步骤S2中加入的催化剂为RuCl[(S,S)-TsDPEN](p-cymene)(cat.1)。
8.根据权利要求7所述的合成(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇的方法,其特征在于,所述步骤S2包括:
在氮气保护的条件下向反应瓶中加入式III化合物、催化剂、有机溶剂;
取三乙胺和甲酸搅拌充分混合,随后加入到反应瓶中,升温至60℃反应一段时间;
加入乙酸乙酯,分离所得有机相并用干燥、过滤,真空浓缩得到化合物I;
优选的,所述有机溶剂为DMF;
优选的,所述反应一段时间为反应过夜;
优选的,所述干燥为用无水硫酸钠干燥。
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