WO2023097696A1 - Method for synthesizing (1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol - Google Patents

Method for synthesizing (1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol Download PDF

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WO2023097696A1
WO2023097696A1 PCT/CN2021/135535 CN2021135535W WO2023097696A1 WO 2023097696 A1 WO2023097696 A1 WO 2023097696A1 CN 2021135535 W CN2021135535 W CN 2021135535W WO 2023097696 A1 WO2023097696 A1 WO 2023097696A1
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benzodioxin
dimethyl
reaction
nitroethanol
nitrite
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Chinese (zh)
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费安杰
叶伟平
周章涛
陈健明
王道功
罗富元
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广东莱佛士制药技术有限公司
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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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  • the invention belongs to the field of organic chemical synthesis, in particular to a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol Methods.
  • (1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol can be used to synthesize (5R)-5-(2, The precursor of 2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, while (5R)-5-(2,2- Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one is an important intermediate in the synthesis of vilanterol, which can be used as a long-acting ⁇ 2 Adrenergic receptor agonist.
  • the present invention develops a process route suitable for industrial production to prepare (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, Using it as an important intermediate, shorten and optimize the synthesis of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxane
  • the operational route of oxazolidin-2-one specifically comprises the following reaction steps:
  • the process route of the present invention starts from the VLO6 intermediate (compound of formula II) in the original process, and sodium nitrite takes place under the catalysis of imidazole-based polyionic liquid (see structural formula 1) SN Substitution reaction occurs to generate the compound of formula III ; followed by reduction under asymmetric catalytic transfer hydrogenation conditions to give (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol (compound of formula I). The compound of formula I can then obtain the VL11 intermediate by further reduction of the nitro group.
  • the process route of the present invention has the following advantages:
  • the amount of chiral catalyst is low, only 0.05 equivalent, and the reaction yield is high, so the reaction catalytic conversion number is high.
  • the by-product of the second step reaction is water, and the treatment of the three wastes is relatively simple, which is beneficial to industrial production.
  • the embodiment of the present invention provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, the The method route is as follows:
  • sodium nitrite, potassium nitrite, etc. can be selected as the nitrite required in the step S1.
  • Sodium nitrite is preferred.
  • the amount of nitrite used is 1.0-2.0 equivalents, preferably 1.5 equivalents. Lower sodium nitrite consumption will slow down the rate of reaction, while a larger amount of sodium nitrite consumption is not conducive to scale-up production.
  • the additives required in the step S2 are N,N-dimethylformamide (DMF), water, etc., preferably DMF.
  • the catalyst required for the step S2 is a chiral diamine/ruthenium catalyst; preferably, the chiral diamine/ruthenium catalyst is selected from at least one of the following: 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). (Scheme1), preferably RuCl[(S,S)-TsDPEN](p-cymene) (cat.1).
  • the embodiment of the present invention provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, the The method route is as follows:
  • the step S1 adds nitrite and imidazole-based polyionic liquid catalyst
  • the nitrite includes sodium nitrite and/or potassium nitrite;
  • the nitrite is sodium nitrite.
  • Sodium nitrite has more sources and is cheaper.
  • the amount of nitrite used is 1.0-2.0 equivalents, preferably 1.5 equivalents.
  • Lower sodium nitrite consumption will slow down the rate of reaction, while a larger amount of sodium nitrite consumption is not conducive to scale-up production.
  • the reaction temperature of S1 and S2 is 40-70°C, preferably 60°C.
  • a lower reaction temperature will slow down the reaction rate, while a higher reaction temperature will increase the side reactions of the reaction.
  • the method includes:
  • the nitrite is sodium nitrite
  • the reaction period is more than 20min, more preferably 20min-30min;
  • the organic solvent is ether
  • the concentrate is purified by silica gel column chromatography
  • the reaction is carried out under an inert gas environment
  • the separating and purifying includes: adding ethyl acetate to the reaction solution, separating the obtained organic phase and drying it with anhydrous sodium sulfate, filtering and concentrating in vacuo.
  • the step S2 needs to add a catalyst and a solvent, and the solvent includes N,N-dimethylformamide (DMF) and/or water, preferably DMF.
  • DMF N,N-dimethylformamide
  • the reason for DMF is The reactants are more soluble in DMF.
  • the catalyst added in the step S2 is a chiral diamine/ruthenium catalyst
  • the chiral diamine/ruthenium catalyst is selected from at least one of the following: 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);
  • the catalyst added in the step S2 is RuCl[(S,S)-TsDPEN](p-cymene)(cat.1).
  • the step S2 includes:
  • the solvent is DMF;
  • the reaction for a period of time is to react overnight
  • the drying is drying with anhydrous sodium sulfate.
  • the structural formula of the imidazole-based polyionic liquid catalyst is:
  • Structural Formula 1 Structure of imidazole-based polyionic liquid catalyst
  • the excellent technical effects brought by the present invention include: Synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2- Nitroethanol, used in the preparation of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
  • the reaction steps can be shortened, and it has the advantages of high reaction conversion number, high atom economy, and suitability for industrial production.
  • the catalyst required for the synthesis route of the present invention is relatively cheap, and the molar yield in the ⁇ -nitroketone reduction step is greater than 85%. It has high asymmetric selectivity and is easy to produce. features.
  • Fig. 1 is the proton nuclear magnetic resonance spectrum of formula I compound.
  • Fig. 2 is the supercritical fluid chromatography (SFC) spectrogram of the compound racemate of formula I.
  • Fig. 3 is the SFC spectrogram of the compound of formula I produced in step 1S2 of Example 1 of the present invention.
  • Structural Formula 1 Structure of imidazole-based polyionic liquid catalyst

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Abstract

Disclosed is a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol. The route of the method is as follows: The method is used for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, which is used in the preparation of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, such that reaction steps can be shortened. The method has the advantages of having a high reaction turnover number, high atom economy, being suitable for industrial production, etc. Compared with a currently reported synthetic route using the asymmetric Henry reaction, the price of a catalyst required for the present synthetic route is relatively low, the molar yield in the step of reducing α-nitroketone is greater than 85%, and the present synthetic route has the characteristics of high asymmetric selectivity and being easy to produce.

Description

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A method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol 技术领域technical field
本发明属于有机化学合成领域，具体涉及一种合成(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。The invention belongs to the field of organic chemical synthesis, in particular to a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol Methods.
背景技术Background technique
(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-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol can be used to synthesize (5R)-5-(2, The precursor of 2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, while (5R)-5-(2,2- Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one is an important intermediate in the synthesis of vilanterol, which can be used as a long-acting β2 Adrenergic receptor agonist.
Figure PCTCN2021135535-appb-000001
Figure PCTCN2021135535-appb-000001
(1R)-1-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-2-硝基乙醇(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol
Figure PCTCN2021135535-appb-000002
Figure PCTCN2021135535-appb-000002
(5R)-5-(2,2-二甲基-4H-1,3-苯并二恶英-6-基)-1,3-恶唑烷-2-酮(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
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：At present, the current synthetic route of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one is as follows Show:
Figure PCTCN2021135535-appb-000003
Figure PCTCN2021135535-appb-000003
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。There are many deficiencies in this route: for example, 1) when ketone is carried out chiral catalytic reduction into alcohol in the second step, a large dose (0.3 single amount) of chiral catalyst (R)-2-methyl-CBS-oxo oxazoboridine; 2) the route contains two steps of protecting groups and deprotecting groups (respectively triethylsilyl and benzyl), and the atom economy is low; 3) the synthetic route has longer steps, including 7 steps.
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。In summary, the development of the pharmaceutical industry urgently needs to develop a low-cost, industrialized process route for the synthesis of the key intermediate (5R)-5-(2,2-dimethyl-4H-1,3- Benzodioxin-6-yl)-1,3-oxazolidin-2-one.
发明内容Contents of the invention
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：The present invention develops a process route suitable for industrial production to prepare (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, Using it as an important intermediate, shorten and optimize the synthesis of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxane The operational route of oxazolidin-2-one specifically comprises the following reaction steps:
Figure PCTCN2021135535-appb-000004
Figure PCTCN2021135535-appb-000004
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S N2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。 The process route of the present invention starts from the VLO6 intermediate (compound of formula II) in the original process, and sodium nitrite takes place under the catalysis of imidazole-based polyionic liquid (see structural formula 1) SN Substitution reaction occurs to generate the compound of formula III ; followed by reduction under asymmetric catalytic transfer hydrogenation conditions to give (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol (compound of formula I). The compound of formula I can then obtain the VL11 intermediate by further reduction of the nitro group.
与原工艺相比，本发明的工艺路线有如下几个优点：Compared with the original process, the process route of the present invention has the following advantages:
(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。(1) The amount of chiral catalyst is low, only 0.05 equivalent, and the reaction yield is high, so the reaction catalytic conversion number is high.
(2)使用转移氢化的方式还原式III化合物，适合放大生产。(2) The compound of formula III is reduced by means of transfer hydrogenation, which is suitable for scale-up production.
(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。(3) The synthesis route is simple, the reaction steps from VL06 to VL11 are reduced from 5 steps in the original process to 3 steps, and it has better atom economy.
(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。(4) The by-product of the second step reaction is water, and the treatment of the three wastes is relatively simple, which is beneficial to industrial production.
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。如下图所示。Currently (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol is mainly synthesized by asymmetric Henry reaction. As shown below.
Figure PCTCN2021135535-appb-000005
Figure PCTCN2021135535-appb-000005
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。In the method reported in document doi:10.1016/j.tetasy.2011.08.008, the route uses relatively expensive (-)-spartine (5600 yuan/gram) as a ligand, and copper (II) chloride di Under the catalysis of hydrate, asymmetric Henry reaction synthesis occurs. Moreover, the equivalents of the ligand and the catalyst are relatively large, both being 0.2 molar equivalents.
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％。In another route (doi:10.1016/j.tetasy.2015.01.001) the in situ generated copper acetate/chiral imidazolin-4-one derivative was used as a catalyst to synthesize (1R)- 1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol. The synthesis of the ligand of this route is relatively complicated and requires six reaction steps to prepare. Moreover, the yield of the product synthesized by the catalytic system is low, only 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。In addition to the above disadvantages, the route of the asymmetric Henry reaction uses explosive nitromethane, which has great safety hazards.
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。Compared with the route for preparing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol by asymmetric Henry reaction, this The catalyst required for the synthetic route of the invention is relatively cheap (189 yuan/g), the molar yield of the α-nitroketone reduction step is greater than 85%, and has the characteristics of high asymmetric selectivity and easy production.
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：The embodiment of the present invention provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, the The method route is as follows:
Figure PCTCN2021135535-appb-000006
Figure PCTCN2021135535-appb-000006
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。According to one embodiment of the present invention, for example, sodium nitrite, potassium nitrite, etc. can be selected as the nitrite required in the step S1. Sodium nitrite is preferred. The amount of nitrite used is 1.0-2.0 equivalents, preferably 1.5 equivalents. Lower sodium nitrite consumption will slow down the rate of reaction, while a larger amount of sodium nitrite consumption is not conducive to scale-up production.
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。According to one embodiment of the present invention, for example, the additives required in the step S2 are N,N-dimethylformamide (DMF), water, etc., preferably 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)。(Scheme1)，优选为RuCl[(S,S)-TsDPEN](p-cymene)(cat.1)。According to one embodiment of the present invention, for example, the catalyst required for the step S2 is a chiral diamine/ruthenium catalyst; preferably, the chiral diamine/ruthenium catalyst is selected from at least one of the following: 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). (Scheme1), preferably RuCl[(S,S)-TsDPEN](p-cymene) (cat.1).
Figure PCTCN2021135535-appb-000007
Figure PCTCN2021135535-appb-000007
手性二胺/钌催化剂的结构Structure of chiral diamine/ruthenium catalyst
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：The embodiment of the present invention provides a method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, the The method route is as follows:
Figure PCTCN2021135535-appb-000008
Figure PCTCN2021135535-appb-000008
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；According to one embodiment of the present invention, for example, the step S1 adds nitrite and imidazole-based polyionic liquid catalyst;
优选的，所述亚硝酸盐包括亚硝酸钠和/或亚硝酸钾；Preferably, the nitrite includes sodium nitrite and/or potassium nitrite;
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。Further preferably, the nitrite is sodium nitrite. Sodium nitrite has more sources and is cheaper.
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。According to one embodiment of the present invention, for example, the amount of nitrite used is 1.0-2.0 equivalents, preferably 1.5 equivalents. Lower sodium nitrite consumption will slow down the rate of reaction, while a larger amount of sodium nitrite consumption is not conducive to scale-up production.
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。According to one embodiment of the present invention, for example, the reaction temperature of S1 and S2 is 40-70°C, preferably 60°C. A lower reaction temperature will slow down the reaction rate, while a higher reaction temperature will increase the side reactions of the reaction.
根据本发明的一种实施方式，例如，所述方法包括：According to one embodiment of the present invention, for example, the method includes:
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；S1: Add water, compound II, imidazole-based polyionic liquid catalyst, and nitrite to the reaction flask, heat up to 60°C and stir; after a period of reaction, stop stirring, add an organic solvent for extraction, combine the obtained organic phases and dry; filter , concentrating the organic phase, purifying the concentrate to obtain compound 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；S2: Add the compound of formula III, a catalyst, and an organic solvent into the reaction flask, take triethylamine and formic acid, stir and mix evenly, then add it to the reaction flask, raise the temperature to 50-70°C for reaction, separate and purify to obtain compound I;
优选的，所述步骤S1中，亚硝酸盐为亚硝酸钠；Preferably, in the step S1, the nitrite is sodium nitrite;
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；Preferably, in the step S1, the reaction period is more than 20min, more preferably 20min-30min;
优选的，所述步骤S1中，所述有机溶剂为***；Preferably, in the step S1, the organic solvent is ether;
优选的，所述步骤S1中，通过硅胶柱层析纯化浓缩物；Preferably, in the step S1, the concentrate is purified by silica gel column chromatography;
优选的，所述步骤S2中，反应在惰性气体环境下进行；Preferably, in the step S2, the reaction is carried out under an inert gas environment;
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。Preferably, in the step S2, the separating and purifying includes: adding ethyl acetate to the reaction solution, separating the obtained organic phase and drying it with anhydrous sodium sulfate, filtering and concentrating in vacuo.
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。According to one embodiment of the present invention, for example, the step S2 needs to add a catalyst and a solvent, and the solvent includes N,N-dimethylformamide (DMF) and/or water, preferably DMF. The reason for DMF is The reactants are more soluble in DMF.
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；According to one embodiment of the present invention, for example, the catalyst added in the step S2 is a chiral diamine/ruthenium catalyst;
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)；Preferably, the chiral diamine/ruthenium catalyst is selected from at least one of the following: 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)。Preferably, the catalyst added in the step S2 is 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：According to one embodiment of the present invention, for example, the step S2 includes:
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；Add formula III compound, catalyst, solvent to reaction flask under the condition of nitrogen protection;
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。Stir and mix triethylamine and formic acid thoroughly, then add them into a reaction flask, heat up to 60°C and react for a period of time; the mixture of triethylamine and formic acid can provide a hydrogen transfer reagent.
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；Ethyl acetate was added, the resulting organic phase was separated and dried, filtered, and concentrated in vacuo to obtain compound I;
优选的，所述溶剂为DMF；Preferably, the solvent is DMF;
优选的，所述反应一段时间为反应过夜；Preferably, the reaction for a period of time is to react overnight;
优选的，所述干燥为用无水硫酸钠干燥。Preferably, the drying is drying with anhydrous sodium sulfate.
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：According to one embodiment of the present invention, for example, the structural formula of the imidazole-based polyionic liquid catalyst is:
Figure PCTCN2021135535-appb-000009
Figure PCTCN2021135535-appb-000009
结构式1：咪唑基聚离子液体催化剂的结构Structural Formula 1: Structure of imidazole-based polyionic liquid catalyst
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。The excellent technical effects brought by the present invention include: Synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2- Nitroethanol, used in the preparation of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one In the method, the reaction steps can be shortened, and it has the advantages of high reaction conversion number, high atom economy, and suitability for industrial production. Compared with the currently reported synthesis route using the asymmetric Henry reaction, the catalyst required for the synthesis route of the present invention is relatively cheap, and the molar yield in the α-nitroketone reduction step is greater than 85%. It has high asymmetric selectivity and is easy to produce. features.
附图说明Description of drawings
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。In order to illustrate the technical solutions of the embodiments of the present invention more clearly, the drawings of the embodiments will be briefly introduced below. Apparently, the drawings in the following description only relate to some embodiments of the present invention, rather than limiting the present invention.
图1是式I化合物的核磁共振氢谱。Fig. 1 is the proton nuclear magnetic resonance spectrum of formula I compound.
图2是式I化合物消旋体的超临界流体色谱(SFC)谱图。Fig. 2 is the supercritical fluid chromatography (SFC) spectrogram of the compound racemate of formula I.
图3是本发明实施例1S2步骤生成的式I化合物的SFC谱图。Fig. 3 is the SFC spectrogram of the compound of formula I produced in step 1S2 of Example 1 of the present invention.
具体实施方式Detailed ways
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。The method for the synthesis of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol of the present invention will be done below in conjunction with specific examples Further clarification. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.
实施例1Example 1
Figure PCTCN2021135535-appb-000010
Figure PCTCN2021135535-appb-000010
S1：SN2取代反应制得α-硝基酮类化合物IIIS1: SN2 substitution reaction to prepare α-nitroketone compound 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***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％。Add water, compound II (285g), imidazole-based polyionic liquid catalyst (0.1g, structural formula as follows), sodium nitrite (104g, 1.5eq.) into the reaction flask, heat up to 60°C and stir. After reacting for 20 min, stop stirring. Diethyl ether was added to extract three times, and the resulting organic phases were combined and dried over anhydrous sodium sulfate. Filter, concentrate the organic phase, and purify the concentrate by silica gel column chromatography to obtain 176g of compound III with a yield of 70%.
Figure PCTCN2021135535-appb-000011
Figure PCTCN2021135535-appb-000011
结构式1：咪唑基聚离子液体催化剂的结构Structural Formula 1: Structure of imidazole-based polyionic liquid catalyst
S2：催化转移氢化制得α-硝基醇类化合物IS2: Preparation of α-Nitroalcohol Compound I by Catalytic Transfer Hydrogenation
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＝7.8Hz,1H),6.95(s,1H),6.78(d,J＝7.8Hz,1H),4.80(s,2H),4.70(s,1H),3.64(d,J＝47.2Hz,2H),1.52(s,6H). Add formula III compound (10g, 1.0eq.), catalyst RuCl[(S,S)-TsDPEN](p-cymene) (1.25g, 0.05eq.), DMF (50mL ). Take triethylamine (8.7mL) and formic acid (3.8mL) and stir for 3 minutes, then add into the reaction flask, heat up to 60°C and react overnight. Ethyl acetate was then added to the reaction solution, and the resulting organic phase was separated and dried over anhydrous sodium sulfate. Filtration and vacuum concentration gave 8.7 g of compound I with a yield of 87% and an ee value of 94.3%. 1 H NMR (600MHz, CDCl3) δ7.10(d, J=7.8Hz, 1H), 6.95(s, 1H), 6.78(d, J=7.8Hz, 1H), 4.80(s, 2H), 4.70( s,1H),3.64(d,J=47.2Hz,2H),1.52(s,6H).

Claims (9)

  1. 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，其特征在于，所述方法路线如下：A method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol, characterized in that the method The route is as follows:
    Figure PCTCN2021135535-appb-100001
    Figure PCTCN2021135535-appb-100001
  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；The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 1, characterized in In step S1, nitrite and imidazole-based polyionic liquid catalyst are added;
    优选的，所述亚硝酸盐包括亚硝酸钠和/或亚硝酸钾；Preferably, the nitrite includes sodium nitrite and/or potassium nitrite;
    进一步优选的，所述亚硝酸盐为亚硝酸钠。Further preferably, the nitrite is sodium nitrite.
  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。The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 2, characterized in That is, the amount of nitrite used is 1.0-2.0 equivalents, preferably 1.5 equivalents.
  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℃。The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 3, characterized in That is, the reaction temperature of S1 and S2 is 40-70°C, preferably 60°C.
  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：The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 4, characterized in In that, the method includes:
    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；S1: Add water, compound II, imidazole-based polyionic liquid catalyst, and nitrite to the reaction flask, heat up to 60°C and stir; after a period of reaction, stop stirring, add an organic solvent for extraction, combine the obtained organic phases and dry; filter , concentrating the organic phase, purifying the concentrate to obtain compound 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；S2: Add the compound of formula III, a catalyst, and an organic solvent into the reaction flask, take triethylamine and formic acid, stir and mix evenly, then add it to the reaction flask, raise the temperature to 50-70°C for reaction, separate and purify to obtain compound I;
    优选的，所述步骤S1中，亚硝酸盐为亚硝酸钠；Preferably, in the step S1, the nitrite is sodium nitrite;
    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；Preferably, in the step S1, the reaction period is more than 20min, more preferably 20min-30min;
    优选的，所述步骤S1中，所述有机溶剂为***；Preferably, in the step S1, the organic solvent is ether;
    优选的，所述步骤S1中，通过硅胶柱层析纯化浓缩物；Preferably, in the step S1, the concentrate is purified by silica gel column chromatography;
    优选的，所述步骤S2中，反应在惰性气体环境下进行；Preferably, in the step S2, the reaction is carried out under an inert gas environment;
    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。Preferably, in the step S2, the separating and purifying includes: adding ethyl acetate to the reaction solution, separating the obtained organic phase and drying it with anhydrous sodium sulfate, filtering and concentrating in vacuo.
  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。Synthetic (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to any one of claims 1-5 The method of the present invention is characterized in that the organic solvent in the step S2 includes N,N-dimethylformamide (DMF) and/or water, preferably 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；The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 6, characterized in In that, the catalyst added in the step S2 is a chiral diamine/ruthenium catalyst;
    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-trimethyl benzene)(cat.2),RuCl[(S,S)-TsDPEN](benzene)(cat.3),RuCl[(S,S)-FsDPEN](p-cymene)(cat.4)；Preferably, the chiral diamine/ruthenium catalyst is selected from at least one of the following: 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)。Preferably, the catalyst added in the step S2 is 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：The method for synthesizing (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to claim 7, characterized in In that, the step S2 includes:
    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；Add formula III compound, catalyst, organic solvent to reaction flask under the condition of nitrogen protection;
    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；Take triethylamine and formic acid and mix them thoroughly, then add them into the reaction flask, heat up to 60°C and react for a period of time;
    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；Ethyl acetate was added, the resulting organic phase was separated and dried, filtered, and concentrated in vacuo to obtain compound I;
    优选的，所述有机溶剂为DMF；Preferably, the organic solvent is DMF;
    优选的，所述反应一段时间为反应过夜；Preferably, the reaction for a period of time is to react overnight;
    优选的，所述干燥为用无水硫酸钠干燥。Preferably, the drying is drying with anhydrous sodium sulfate.
  9. 根据权利要求2-8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，所述咪唑基聚离子液体催化剂的结构式为：Synthetic (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-nitroethanol according to any one of claims 2-8 The method is characterized in that, the structural formula of described imidazole-based polyionic liquid catalyst is:
    Figure PCTCN2021135535-appb-100002
    Figure PCTCN2021135535-appb-100002
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