• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to the cross-coupling reaction of 2-bromo-1-phenylindenes with phenylacetylenes or propargyl alcohol. The cross-coupling reaction utilizes a palladium catalyst with triphenylphosphine in the absence of a copper co-catalyst. The reaction is carried out with pyrrolidine as a base in water at 120 ° C.
    公开号:CH709073B1
    申请号:CH00563/15
    申请日:2012-10-24
    公开日:2018-06-29
    发明作者:A Batey Robert；Gregory Rosocha Yaroslav
    申请人:Gregory Rosocha Yaroslav；
    IPC主号:
    专利说明:

    Description SUMMARY OF THE INVENTION [0001] This invention relates to the synthesis of various cross-linked products (yield of 20 to 80%) by reaction between 2-bromo-1-phenyl substituted indenes with phenylacetylene or alcohol. propargyl. The reaction is conducted in water in the presence of palladium chloride, triphenylphosphine and pyrrolidine as a base at 120 ° C.
    It has not been described any method and / or protocol or example which implements the cross coupling between an alkyne and an indene.
    The conventional synthesis protocols which implement the coupling of alkynes involve the use of organic solvents and / or halogens which, from the point of view of safety, are very dangerous because of their explosive nature and their toxicity (ie, carcinogenic, teratogenic). This process is an alternative to the use of these solvents since the reaction is carried out in water, which is the safest and most environmentally friendly solvent.
    Current processes require the use of copper to regenerate the active palladium catalyst throughout the reaction. The above reaction does not involve the use of copper, which is toxic. The non-use of copper eliminates exposure problems during the conduct of the process. In addition, the use of copper is expensive in the industrial context and eliminating the need for copper eliminates the costs associated with its use.
    The method of cross-coupling 2-bromo-indenes with alkynes of the present invention is distinguished in particular by that it is carried out in water and without copper.
    The method of the present invention can be implemented by means of a circulating microreactor device with the following advantages: - These circulating microreactor devices are more efficient than conventional discontinuous synthesis because they allow to increase reaction efficiency by minimizing waste byproducts. These microreactors make it possible to conduct chemical reactions in a shorter time. - These devices are usually fully automated and controlled by a computer that allows the rapid optimization of a reaction by allowing to modify variables such as temperature, flow, concentration and time. Such a device may be a compact and modular small reactor that has a chemical output rate that is constant (i.e., 1 g / 1 min-1 g / h). To achieve large scale production, the devices are "assembled" rather than "large scale" (ie, 1 device makes 1 g / min, therefore after 24 hours = 1.44 kg, after 365 days = 525.6 kg If 50 devices are operational, then 26.2 tons of product are obtained each year). Therefore, due to the assembly process, different synthetic procedures are not required on a larger scale (ie, typically, a small batch scale synthesis (1 g) differs large scale synthesis (1 tonne) of the same product because different materials will be needed due to potential hazards and safety issues associated with the use of a large quantity of this chemical. have a scaling up team that is aware of such risks associated with these chemicals that is specialized in the large-scale production of synthons of pharmaceutical agents and chemicals.The microreactor device would require a team of scaling of the process to implement large-scale production of a drug or a drug chemical oduit.
    The method of the present invention can be used for the generation of new base compounds, the manufacture of generic drugs, chemical synthons, and their increase in scale.
    [0008] A circulating microreactor system is known as H-Cube, marketed by Thales-Nano. The H-Cube allows the user to conduct hydrogenations without the need for a hydrogen tank and can process up to half a kilogram of material / day. The unit generates hydrogen by electrolysis of water, collects the generated hydrogen, and uses it throughout the hydrogenation. It has been shown that the product is very effective and gives better results than discontinuous processes. In addition, the absence of a hydrogen tank eliminates any risk of explosion which is a major concern when conducting hydrogenations. In addition, the unit is interfaced with a computer, which automatically achieves optimal conditions (ie, temperature, flow, concentration, in terms of product yield). The H-Cube exists in a new, larger version, which is capable of reaching higher production volumes. Other companies provide microreactor systems but these are not designed for specific processes (ie, a specific reaction class such as hydrogenations for which the H-Cube is designed) but are rather available as a kit that the customer can use on his current chemistry to determine if he has a benefit in his case.
    The present invention allows many uses and can bring value for users because of their applicability in different chemical industries. It is unique and has many advantages in terms of safety and efficiency.
    The process that is the subject of the present invention is characterized in particular by the following elements: [0010] The alkyne may be phenylacetylene or propargyl alcohol.
    The basic solvent mixture is water containing a base.
    The base is pyrrolidine or pyridine.
    The method can be implemented in a sealed tank.
    Said tank may be a microreactor and / or a flow device comprising a technical design feature consisting of channels and / or prefabricated grooves with dimensions in the range of 1 nanometer to 200 micrometers.
    The process can be carried out in the absence of copper and / or compounds forming micelles.
    [0015] Indenes are naturally occurring compounds isolated from coal tar / crude oil refining fractions.
    The main uses of indenes are the production of indene resin, which is the starting material for many plastic products (ie, floor tiles). They are also used as thermal imaging material for stencil marking.
    The indenes possess many desirable properties and are also used as biologically active pesticides incorporated into animal plastic collars.
    Indenes are pharmaceuticals available for the treatment of HIV (Crixivan-Merck,) and pain (Sulindac). Indenes are also used as follows: - For the treatment of cerebrovascular diseases Indeloxazine (Japan). - As estrogen receptor agonists. As selective modulators for peroxisome proliferator activated receptor (PPAR). - As anti-inflammatory pharmaceutical agents - Sulindac - Clinoril - Merck United States and United Kingdom. - As agrochemical antifungal agents and production of coatings. - For the treatment of precancerous and cancerous lesions. - As muscarinic agonists (Eli Lilly) (manufactured via osmium catalysis). As anticoagulants.
    Alkynes are petrochemicals for chemical raw materials.
    Alkynes are components of different rubbers and plastics.
    They can be used as thermosetting and insulating resins.
    Some alkynes have biological activity and are used as pharmaceutical agents.
    They are mainly used as synthons for other compounds.
    The following alkynes are known to have a biological activity: 1) Efaviren (Sustiva), HIV inhibitor pharmaceutical agent. 2) Terbinafine (Lamisil, Zimig), antifungal agent. 3) Esperamicin and calichéamicine are two of the most powerful antitumor agents available.
    The products of the present invention are in particular the following:
    权利要求:
    Claims (4)
    [1]

    claims
    A chemical process comprising reacting 2-bromo-1-phenylindene with phenylacetylene or propargyl alcohol in a mixture of basic solvents in the presence of palladium chloride and triphenylphosphine to obtain one of the following indenes:

    characterized in that the base solvent is water containing a base, the base being selected from pyrrolidine or pyridine, in that said process is conducted at 120 ° C, and in that said process is carried out in a tank in an aerobic or anaerobic atmosphere.
    [2]
    2. Method according to claim 1, characterized in that said vessel is a microreactor.
    [3]
    3. Method according to any one of the preceding claims 1 or 2, characterized in that it is practiced in the absence of copper and / or compounds forming micelles.
    [4]
    4. Method according to any one of claims 1 or 2, characterized by the following reaction scheme:

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    同族专利:
    公开号 | 公开日
    CA2890993C|2021-06-29|
    WO2014064478A1|2014-05-01|
    US9932283B2|2018-04-03|
    CA2890993A1|2014-05-01|
    US20150291492A1|2015-10-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2008037604A1|2006-09-25|2008-04-03|Università Degli Studi Di Siena|Novel polybenzofulvene derivatives, synthesis and uses thereof|
    法律状态:
    2015-10-15| AZW| Rejection (application)|
    2018-03-29| PK| Correction|Free format text: RECTIFICATION INVENTEUR |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/IB2012/002075|WO2014064478A1|2012-10-24|2012-10-24|The cross coupling of 2-bromo-1-phenyl indenes with phenyl acetylenes and other substituted acetylenes in water|
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