• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    The present invention relates to a process for preparing 1-aryl-2-bromo-substituted indenes and 1-phenyl-2-bromo-substituted indenes which may have different functional groups present around the indene ring and / or the aromatic ring and / or of the phenyl ring. The indenes are prepared by using 1,2-biaryl-gem-dibromocyclopropane and / or corresponding 1,2-biphenyl-gem-dibromocyclopropanes and / or 1-aryl-2-phenyl-gem-dibromocyclopropanes and using a metal salt, a solvent, a low temperature.
    公开号:CH709072B1
    申请号:CH00562/15
    申请日:2012-10-24
    公开日:2018-08-15
    发明作者:Rosocha Gregory；A Batey Robert
    申请人:Rosocha Gregory；
    IPC主号:
    专利说明:

    Description
    Description of the invention The present invention consists of a process for the manufacture of 1-phenyl-2-bromoindenes from 1,2-biarylgem-dibromocyclopropane, a metal salt or a mixture of salts with low temperature. The process is carried out in the presence of a solvent in a tank which can be closed.
    In particular, in the process of the present invention, where the 1,2-biaryl-gem-dibromocyclopropane can have a functional group such as chloro, nitro, methyl, on a single aryl ring in any position or on both aryl rings in any position, or have no functional groups on one aryl ring or have no functional groups on both aryl rings.
    The metal salt used in the process of the present invention can be silver tetrafluoroborate. Alternatively, the metal salt can be a salt containing a triphenylcarbenium cation or a mixture of salts containing a triphenylcarbenium cation in stable form.
    The solvent of the present invention is preferably 1,2-dichloroethane.
    The process according to the present invention can be carried out at a temperature in the range from 0 ° C to 100 ° C. In particular, it can last less than 30 minutes at 65 ° C.
    The present invention also includes derivatives of 1-phenyl-2-bromoindenes and their pharmaceutically acceptable salts prepared according to the process described here. In particular, the derivatives of 1-phenyl-2-bromoindenes prepared are for example:
    - 2-bromo-1-phenyl-1 H-indene,
    - 2-bromo-5-methyl-1- (m-tolyl) -1 H-indene,
    - 2-bromo-7-methyl-1- (m-tolyl) -1 H-indene,
    - 2-bromo-4-chloro-1 - (2-chlorophenyl) -1 H-indene,
    - 2-bromo-6-methyl-1- (p-tolyl) -1 H-indene,
    - 2-bromo-6-chloro-1 - (4-chlorophenyl) -1 H-indene,
    - 2-bromo-4-methyl-1-phenyl-1 H-indene,
    - 2-bromo-1 - (o-to ly l) -1 H-indene,
    - 2-bromo-1 - (p-to ly l) -1 H-indene,
    - 2-bromo-6-methyl-1-phenyl-1 H-indene,
    - 2-bromo-5,7-dimethyl-1-phenyl-1 H-indene,
    - 2-bromo-1 - (3,5-dimethylphenyl) -1 H-indene,
    - 2-bromo-3- (3-nitrophenyl) -1 H-indene.
    Process for preparing highly substituted indenes using metal salt catalysts [0006] Synthesis of 2-bromoindenes (1-4) from the corresponding 1,2-biaryl-gem-dihalogenocyclopropanes, using silver tetrafluoroborate in 1,2 -dichloroethane at 65 ° C. The reaction involves a disrotatory 2π electrocyclic decyclization of the cyclopropyl group, facilitated by the precipitation of silver bromide (AgBr) to form the intermediate 1,3-substituted allyl cation which undergoes a 4π conrotatory electrocyclic cyclization reaction to form 2-bromo-1-biphenyl substituted indenes.
    Scheme 1 [0007] Synthesis of 2-bromoindenes from gem-dihalogenocyclopropanes
    3 4
    Diagram 2 [0008] Electrocyclization of symmetrical gem-dibromocyclopropanes to form indenes
    CH 709 072 B1

    3.1 - Novelty and uniqueness of the invention [0009] 1) There are no other methods and / or protocols for synthesizing highly 1,2-substituted indenes involving the use of silver salts. Other processes involve the use of very strong acids which are very dangerous due to their corrosive nature or toxic metallic catalysts.
    2) The method involves a cascaded electrocyclization mechanism which is a very efficient reaction with a high yield, and which has never been used for the synthesis of indenes.
    3) The end products are part of a chemical class of indenes which have been shown to have many desirable medicinal properties (i.e. anticancer, insulin modulators, cardiovascular, anti-obesity). They have heart structures similar to those of vitamin D.
    3.2 - Indenes 1) The indenes are natural compounds isolated from coal tar fractions and / or from the refining of crude oil.
    2) Many uses of indene reside in the production of an indene resin which is the starting point for many plastic products (namely floor tiles). They are also used as thermal imaging material for handouts.
    3) Indenes have been found to have many desirable properties and are also biologically active, being used as pesticides incorporated in plastic collars for animals.
    4) Indenes are pharmaceutical substances available for the treatment of HIV (Crixivan - Merck, annual income in 2008: 275 million dollars) and pain (Sulindac).
    3.3 - Indenes which have a biological activity [0016] 1) Used for the treatment of cerebrovascular diseases - Indeloxazine (Japan).
    2) Estrogen receptor agonists.
    3) Selective modulators of the peroxisome proliferator activator receptor (PPAR).
    4) Anti-inflammatory pharmaceutical agents - Sulindac - Clinoril - Merck, United States and United Kingdom.
    5) Anti-fungal agents.
    6) Used for the treatment of precancerous and cancerous lesions.
    7) Used as muscarinic agonists (Eli Lilly) (produced by osmium catalysis).
    8) Used as anti-coagulants.
    Use of a device for carrying out the processes A flow device in microreactors, capable of carrying out the above processes, would be very beneficial and advantageous for the consumer, for several reasons:
    1) This device should allow the handling and recycling of osmium, helping to minimize the costs associated with the purchase, storage, use and treatment of osmium and its corresponding waste , and by solving many environmental problems.
    2) This device should minimize human exposure to osmium and the corresponding waste since it is confined in the device. This is an advantage for the consumer since it provides an additional level of security.
    3) These flow devices in microreactors have been found to be more efficient than a conventional batch synthesis by having the capacity to increase the reaction yield by minimizing waste by-products. 4) These microreactors have also been found to allow the completion of chemical reactions in a shorter time.
    CH 709 072 B1 5) These devices are usually fully automated and controlled by a computer which allows rapid optimization of a reaction by allowing changes in variables such as temperature, flow rate, concentration, and time .
    6) The device is a small compact modular reactor which has a constant chemical yield (ie 1 g / 1 min-1 g / h). To obtain large-scale production, the devices are “increased” rather than “enlarged” (that is, 1 device produces 1 g / min, therefore 1.44 kg after 24 hours, 525.6 kg after 365 days. If 50 devices are operational, then 26.2 tonnes of product are obtained each year). Therefore, due to the method of increasing the number, different synthesis procedures are not necessary for a larger scale (i.e., typically a small batch scale synthesis [1 g] differs from a large-scale synthesis [1 tonne] of the same product because different materials will be required due to potential risks and safety considerations associated with the use of a large amount of such a chemical. Pharmaceutical companies usually have a team to scale up a process, which is aware of the risks associated with these chemicals and which is specialized in the large production of pharmaceuticals and blocks of chemical construction). The microreactor device should not need a process scale-up team to carry out the large-scale production of a drug or chemical.
    8) The process allows the synthesis of a large library of isoquinolines and other similar products, allowing access to more than 5000 billion isoquinoline products by varying the starting materials indenes and amines.
    9) The method can be used for the generation of new lead compounds, the manufacture of generic drugs, chemical building blocks, and their scaling up.
    Conclusion The above invention offers many uses and can provide added value to consumers because of their applicability in different chemical industries. It is unique and offers many advantages in terms of safety and performance.
    CH 709 072 B1 [0034]
    AT B VS 8 fry B r C jl · / Br Me. VQ ~ 8r 0 Me V / Chemical formula: CisHuBr Me Chemical formula: CizHisBr Exact mass: 270.00 Chemical formula: CwHisBr Exact mass: 298.04 Molecular Weight: 271.15 Exact mass: 284.02 Molecular Weight: 299.20 Elemental analysis: C, 66.44; Molecular Weight: 285.18 Elemental analysis: C, 68.24; H, 4.09; Br, 29.4 Elemental analysis: C, 67.39; H, 5.05; Br, 26.7 H, 4.59; Br, 28.02 9 LXf Br fi F // ~ BrvX > 5 = Z Me Go/ Go-/ fv'e Chemical formula: CisHuBr MeChemical formula: CieHieBr Chemical formula: CnHisBr Exact mass: 270.00 Exact mass: 298.04 Molecular Weight: 271.15 Exact mass: 284 02 Molecular Weight: 299.20 Elemental analysis: C, 66.44; Molecular Weight: 285.18 Elemental analysis: C, 68.24;H, 5.05; Br, 26.7 H, 4.09; Br, 29.4 Elemental analysis: C, 67.39; H, 4.59; Br, 28.02 10 i lV Br YW 8r {FXX-Br your O 0 Me / Y Chemical formula: CwHnBr Chemical formula: CieHnBr Exact mass: 284.02 Me*'/ Exact mass: 284.02 Chemical formula: CizHisBr Molecular Weight: 285.18 Molecular Weight: 285.18 Exact mass: 298.04 Elemental analysis: C, 67.39;H, 4.59; Br, 28.02 Elemental analysis: C, 67.39;H, 4.59; Br, 28.02 Molecular weight: 299.20 Elemental analysis: C, 68.24;H, 5.05; Br, 26.7 11 me ^ ffXX- Br UQ -8r O 0 o 2 n ^ Chemical formula: CvHisBr Exact mass: 298.04Molecular Weight: 299.20 Chemical formula: CisHioBrN02 Exact mass: 314.99Molecular Weight: 316.15 Elemental analysis: C, 68.24; H, 5.05; Br, 26.7 12 jf jTy ~ Br This CQ ~ eri C! ~~ / ~ T V / Cl Go/ Me Chemical formula: C-isHeBrCiz Chemical formula: CisHgBrCiz Chemical formula: CvHisBr Exact mass: 337.93 Exact mass: 337.93 Exact mass: 298.04 Molecular Weight: 340.04 Molecular Weight: 340.04 Molecular Weight: 299.20 C, 52.98; H, 2.67; Br, 23.50; Cl, C, 52.98; H, 2.67; Br, 23.50; Cl, Elemental analysis: C, 68.24; 20.85 20.85 H, 5.05; Br, 26.7
    CH 709 072 B1
    AT B VS 13 (ATA- Br This jfyy Br and Vaz Chemical formula: CisHgBrCb Chemical formula: CisHgBrCb Exact mass: 337.93 Exact mass: 337.93 Molecular Weight: 340.04 Molecular Weight: 340.04 C, 52.98; H, 2.67; Br, 23.50; Cl, C, 52.98; H, 2.67; Br, 23.50; Cl, 20.85 20.85
    权利要求:
    Claims (4)
    [1]
    1. Process for the manufacture of 1-phenyl-2-bromoindenes from 1,2-biaryl-gem-dibromocyclopropane, of a salt selected from silver tetrafluoroborate, a salt containing a triphenylcarbenium cation and a mixture of salts containing a triphenylcarbenium cation in stable form, at a temperature between 0 ° C and 100 ° C, the 1,2biaryl-gem-dibromocyclopropane can have a functional group such as chloro, nitro, methyl, on a single aryl ring in any which position or on the two aryl rings in any position, or have no functional group on an aryl ring or have no functional group on the two aryl rings, the process being carried out in the presence of the solvent 1,2 -dichloroethane in a tank which can be closed.
    [2]
    2. The method of claim 1, wherein the reaction is carried out for less than 30 minutes at 65 ° C.
    [3]
    3. 1-Phenyl-2-bromoindenes and their pharmaceutically acceptable salts prepared according to the method of claim 1.
    [4]
    4. 1-phenyl-2-bromoindenes prepared according to the method of claim 1, wherein 1-phenyl-2-bromoindene is 2-bromo-1-phenyl-1 H-indene, 2-bromo-5-methyl-1 - (m-tolyI) -1 H-indene, 2-bromo-7-methyl-1 - (m-tolyl) -1 H-indene, 2-bromo-4-chloro-1 - (2-chlorophenyl) -1 H-indene, 2-bromo-6-methyl-1 - (p-to ly I) -1 H-indene, 2-bromo-6-chloro-1 - (4chlorophenyl) -1 H-indene, 2-bromo- 4-methyl-1-phenyl-1 H-indene, 2-bromo-1 - (o-tolyI) -1 H-indene, 2-bromo-1 - (p-tolyI) -1 H-indene, 2-bromo -6-methyl-1-phenyl-1 H-indene, 2-bromo-5,7-dimethyl-1-phenyl-1 H-indene, 2-bromo-1 - (3,5dimethylphenyl) -1 H-indene, or 2-bromo-3- (3-nitrophenyl) -1 H-indene.
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    引用文献:
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    法律状态:
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    优先权:
    申请号 | 申请日 | 专利标题
    PCT/IB2012/002074|WO2014064477A1|2012-10-24|2012-10-24|Process to make highly substituted indenes using metal slat catalysts|
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