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    • 专利摘要:
    The present invention relates to a procedure for the synthesis of tetrahydroisoquinolines from indene substituted with 2-methyl-1-phenyl. The method uses the use of osmium tetroxide to cleave the double bond of indene to form the keto-aldehyde product, which is then combined with a substituted amine to form the substituted isoquinoline. Isoquinolines may be useful as industrial products in the chemical, agrochemical, oil and gas industry, and also useful as drugs in the pharmaceutical industry.
    公开号:CH709071B1
    申请号:CH00561/15
    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
    Introduction [0001] The present invention relates to the synthesis of tetrahydroisoquinoleins from 2-methyl-1-phenyl substituted indenes. SUMMARY OF THE INVENTION [0002] The invention particularly relates to the use of osmium tetroxide in the oxidative cleavage of the indene 1 double bond to form the corresponding keto-aldehyde product in 45% yield. 65% (Invention 1a). This keto-aldehyde 2 is then used in the reductive amination protocol with primary amines to synthesize 2,3,4-substituted tetrahydroisoquinolines 3 with yields of 28% to 99% (invention 1b). (10 examples) O, RNH2 (1.0 eq.)
    K2OsO4 / H AcOH (1.2eq) R
    THF: H 2 O (Me 2 H) (Na 2 NC) Na 2 NC (2.0 eq.) The method described employs the synthesis of highly isoquinolines. substituted (3) with high yields from the corresponding substituted indene (1) There are currently no methods and / or protocols for making isoquinoline products having the substitution profiles present in isoquinoline final.
    The method uses the use of osmium tetroxide to cleave the double bond of indene to form the keto-aldehyde product (2) which is combined with the corresponding substituted amine to form the substituted isoquinoline. . [0005] There is no method for effecting oxidative cleavage on an indene scaffold using osmium.
    [0006] Osmium is a catalytic metal that is very useful in synthesis because of the reactions that can be carried out (that is to say, oxidative cleavage, dihydroxylations, aminohydroxylations). These reactions are used by many pharmaceutical companies and companies that synthesize synthons for the pharmaceutical industry (that is, third-party synthesis subcontractors). The only alternative to osmium for performing an oxidative cleavage reaction involves the use of ozone which is a toxic, explosive and dangerous gas to use. An ozone generator is needed to generate ozone for the reaction, and the reactions are not selective and lead to many unwanted by-products, leading to an increase in waste generation, and a decrease in reaction efficiency.
    The isoquinolines have many medicinal properties that allow them to be useful products for the treatment of different medical conditions. The high biological activity of isoquinolines allows them to be attractive targets for pharmaceutical companies. There are currently many isoquinoline products used as viable treatments. Some therapeutic indications are notably set out below: Vasodilators such as papaverine are isoquinolines which are currently used pharmaceutical agents, sold under the brand names Pavacap, Pavadil (United States), Artegodan, Panergon (Germany) , Cardiospan, Papaversan (France), Cardioverina (countries outside Europe and the United States). - Hypertension and congestive heart failure such as quinapril, marketed under the brand name: Ac-cupril (Pfizer). - Anesthetics such as dimethisoquine. - Antifungal agents. - Broad spectrum microbicides. - Surfactants and detergents without phosphate.
    [0008] Indenes are naturally occurring compounds isolated from coal tar fractions / crude oil refining.
    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).
    The method of the present invention can be conducted using a circulating microreactor device with the following advantages: - Such a device allows the handling and recycling of osmium, which helps reduce the costs associated with the purchase, storage, use and disposal of osmium and its associated wastes, thereby solving many environmental problems. Such a device minimizes human exposure to osmium and the corresponding waste since it is confined in the device. This is beneficial for the user since an additional level of security is obtained. These circulating microreactor devices are more efficient than conventional batch synthesis because they 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. The device is 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 of processes 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 process augmentation team to implement large-scale production of a drug or chemical. The process of the present invention makes it possible to synthesize a large library of isoquinolines and other similar products allowing access to more than 5 isoquinoline product triols by varying the starting materials of indene and amine. 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 scaling up.
    Such a circulating microreactor is already 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). 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 process of the present invention is further distinguished by the following elements: [0012] The process is used for the low temperature upgrading of petroleum products, coal tar and coal oil containing carbon dioxide. indene in mass amounts in the range of 0.0010% to 99.9% per gram of the specified starting material of petroleum or coal tar or coal oil.
    Derivatives of 1,2,3,4-tetrahydroisoquinolines (3) can be obtained by the process in their basic forms, or acids.
    The process may be carried out in a sealed reaction vessel, such as a batch reactor, or in a circulating microreactor capable of maintaining an anaerobic or aerobic atmosphere.
    The flow of reaction fluid can be modified and regulated, as well as the residence time in the channels or prefabricated grooves.
    The present invention also covers 1,2,3,4-tetrahydroisoquinoline derivatives (3) manufactured according to the method described. Such a derivative can be used in the chemical, agrochemical, oil and gas industry or as a medicine.
    The described invention allows many uses and can be applied in different chemical industries. It is unique and has many advantages in terms of safety and efficiency.
    The derivatives of the present invention are in particular the following: 92% 98: 2 49% 98: 2
    Chemical formula: C17H19N
    Chemical formula: C26H22N2
    Exact Mass: 237.15
    Exact Mass: 362.18
    Molecular weight: 237.34
    Molecular weight: 362.47 ° C, 86.03; H, 8.07; N, 5.90 ° C, 86.15; H, 6.12; N, 7.73 T CCa "1 -O 1 62% 95: 5 4% 73-99%
    Chemical formula: θ ^: 2
    Chemical formula: C24H25N,, ..
    C18H21N Chemical formula: C22H21N
    Exact mass: 327,20
    Exact Mass: 251.17 Exact Mass: 299.17
    Molecular weight: 327.46 .......
    Molecular weight: Molecular weight: 299.41 C, 88.03; H, 7.70; N, 4.28, 251.37 ° C, 88.25; H, 7.07; N, 4.68 C, 86.01; H, 8.42; N, 5.57
    权利要求:
    Claims (8)
    [1]

    iwcxr ;, ··, οπ (| y ν MLa J! 85% C3 72% 98: 2 90:10 _ il. ·· 75% Formule chimique: C22H20FN Formule chimique: M C2QH25N "Mass exacte: 317,16" " 25 "Q," Formule chimique: C23H23IMO poids moiécu | aire: 317,40 mass exacte: 279,20 ,, i "" mass exacte. 329,18 r-> po nr. Ij o oc cc qq. M Poids moléculaire C '83.25' H '6.35' F '5.99' N 'Poids moléculaire: 329.43 4 279 42 24.41'C, 83.85; H, 7.04; N, 4, 25; O, C, 85.97; H, 9.02; N, RR 4.86 5.01 4 (Γ ^ Ύ ^ ΝΧ ^ ΊΓ ^ 'γγΝ ° 2 Me N <χ <ίίΛγΛ *' Μβ 72% C j) 95: 5 noo / Formule chimique: "M 70:30 C23H23N Formule chimique: C22H20N2O2 Mass exacte: 313,18 ,, x mass exacte: 344,15 Poids moléculaire: _., .., o. ... Poids moléculaire: 344.41 313 44 'C, 76.72; H, 5.85; N, 8.13; O, C, 88.13; H, 7.40; N, g 2θ 4.47 Revendications
    1. Procédé chimique pour la synthèse de dírivés de 1, 2, 3, 4-tetrahydroisoquinolines (3), à partir du 2-methyl-1-phenylene-lindène (1) and one of the primary types of RNH2,





    AA A. V / y Me A. U A 3 1 où R dénote un substitute sélectionné parmi methyl, ethyl, butyl, phenyl, benzyl, phénéthyl, nitrophényl, methoxyphényl, et fluorophényl; the procédé comprenant une première étape de clivage oxydatif, suivie d'une seconde étape d'amination réductrice, caractérisé en ce que: l'étape de clivage oxydatif est réalisée en présence d'un sel d'osmium, et d'un periodate, en ce que l'étape de clivage oxydatif conduit au céto-aldéhyde (2), impliqué dans la seconde étape d'amination réductrice: □ Άή A'A 'o Il, K j Me î ff AA 2 et en ce que la seconde étape d'amination réductrice est réalisée en présence de cyanoborohydrure de sodium (NaBH3CN).
    [2]
    2. Procédé selon la revendication 1, où ledit sel d'osmium est l'osmate de potassium.
    [3]
    3. Procédé selon la revendication 2, où l'osmate de potassium est utilisé dans des quantité catalytiques ou stoechiométriques.
    [4]
    4. Procédé selon l'une quelconque des revendications précédentes caractérisé par les conditions réactionnelles suivantes: O. RNH2 (1.0 eq.) _ K2OsO4 AcOH (1.2eq4 jT k _ ,, A THF: H O if P MeOH (Q.2M > ff Ά N 'kyjk- / --k Λ - "- Uk A NalO4 T NaBH3CN <2.0 eq.)" "J Me vk AA, 1 2 3 où R dénote les substitutes décrits dans la revendication 1.
    [5]
    5. Procédé selon l'une quelconque des revendications précédentes, où les dérivés de 1,2,3,4-tetrahydroisoquinoléines (3) sont obtenus sous leurs formes basiques ou acides.
    [6]
    6. Procédé selon l'une quelconque des revétications précédentes, caractérisé en ce qu'il est exécuté dans une cuve de réaction scellée, quéun réacteur discontinué, ou dans un microréacteur à circulation pouvant maintenir une atmospheree anaérobie ou aérobie.
    [7]
    7. Dérivé de 1, 2, 3, 4-tetrahydro-isoquinolines (3) is a self-proclaimed product of rev. 1 à 6.
    [8]
    8. Dérivé selon la revendication 7, caractérisé en ce que le dérivé est sélectionné parmi les composés suivants:

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    同族专利:
    公开号 | 公开日
    US20150284332A1|2015-10-08|
    CA2889118C|2020-12-15|
    WO2014064476A1|2014-05-01|
    US9902699B2|2018-02-27|
    CA2889118A1|2014-05-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2015-10-15| AZW| Rejection (application)|
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/IB2012/002070|WO2014064476A1|2012-10-24|2012-10-24|The synthesis of tetrahydroisoquinolines from 2-methyl-1-phenyl substituted indenes|
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