BATEY ROBERT A (CA)
MILLER ET AL.: "Synthesis of Isoquinolines from Indenes", THE JOURNAL OF ORGANIC CHEMISTM, vol. 45, no. 26, 1980, pages 5312 - 5315
| Claims 1 . A chemical process (Figure 1 ) that involves the use of a solvent, oxidant, indene, and metal salt to form 1 ,2,3 ,4-tetrahydroisoquinol i nes (Figure 2). 2. The oxidant in claim 1 is a periodate salt ox idant such as sodium periodate (NalC^). but is not lim ited to the use of only periodate oxidants. 3. The oxidant in claim 1 can be a m ixture of oxidizing chemicals with ox idizing properties simi lar to periodate oxidants. 4. The indene component in claim 1 is a coal tar and/or petroleum derived chemical including al l natural methyl and phenyl containing isomers that are found in coal tar and/or petroleum . 5. The metal salt in claim 1 is an osmium salt that has the formula ( 2OSO4) that can be used in catalytic and/or stoichiometric amounts. 6. The solvent in claim I , 2, 3, 4 is a water containing solvent system that can additional ly contain any organic solvent in any amount. 7. The process in claim 1 is a process for low temperature chemical upgrading of petroleum and/or coal tar and/or coal oi l products containing indene in mass quantities ranging from 0.00000001 %-99.99999% per gram of the specified petroleum oil and/or coal tar and/or coal oil starting material but not limited to. 8. The process can form 1 ,2,3,4-tetrahydroisoquinolines (Figure 2) from 2-methyl- l -phenyl indenes and their corresponding basic, acidic, and al l other polymorph ic forms with chem ical yields and process efficiencies ranging from 0.000001 %-99.999999%. 9. The 1 ,2,3,4-tetrahydroisoquinol ines obtained can be used as useful industrial products for the chemical agrochemica! , oil and gas industry and have been shown to be usefu l medicaments for the pharmaceutical industry. 1 0. The reaction vessel in claim 1 can be any vessel that is capable of being sealed but not limited to a vessel . 1 1 . The reaction vessel in claim 1 can be a batch reactor, microreactor and/or flow apparatus bearing a design engineering functional ity consisting of pre-fabricated channels and/or grooves with dimensions ranging from 1 nanometer to 200 micrometers but not lim ited to these dimensions. 1 2. The reaction vessel in claim 1 can have the chem ical reaction fluid passing inside the inner channels and/or grooves with distances travel led by the reaction fluid ranging from 1 femtometer to 1 000 meters but not l im ited to these dimensions or combinations thereof. 1 3. The reaction vessel in claim 1 is capable of obtaining temperature ranges from - 1 50°C to 1 000°C but not limited to these ranges. 14. The reaction vessel in claim 1 is capable of altering and/or regulating the rate of reaction fluid flow and the residence times within the prefabricated channels and/or grooves. 1 5. The reaction fluid flow rate in claim 14 can be within the ranges of 0.0001 mL/minute- 500L/min but not limited to these ranges. 16. The residence times in claim 14 can be within the ranges of 0.001 seconds- 1 00 hours but not l imited to these ranges. |
| AMENDED CLAIMS received by the International Bureau on 27 January 2014 (27.01.2014) 1. A chemical process that uses a solvent blend, oxidant, indene, and metal salt to form 1 ,2,3,4- tetrahydroisoquinolines using a reaction vessel. 2. The oxidant in claim 1 is a mixture containing a periodate salt oxidant such as sodium periodate. 3. The oxidant in claim 1 can be a mixture of oxidizing chemicals with oxidizing properties similar to periodate oxidants. 4. The indene in claim 1 can be a coal tar or petroleum derived chemical that includes all methyl and phenyl substituted isomers. 5. The metal salt in claim 1 is an osmium salt that can contain potassium osmate and can be used in catalytic and stoichiometric amounts. 6. The solvent blend in claim 1 is a water containing solvent system that contains an organic solvent. 7. The process in claim 1 can be used for low temperature upgrading of petroleum, coal tar and coal oil products that contain indene in mass quantities ranging from 0.0010%-99.9% per gram of the specified petroleum or coal tar or coal oil starting material. 8. The process in claim 1 can be used to make 1 ,2,3,4-tetrahydroisoquinolines and their corresponding basic, acidic, and all other polymorphic forms using 2 -methyl- 1 -phenyl indenes with chemical yields ranging from 0.0100%-99.99%. 9. The 1,2,3,4-tetrahydroisoquinolines of the general structure I made from the process in claim 1 can be used as useful industrial products for the chemical, agrochemical, oil and gas industry and can be useful medicaments for the pharmaceutical industry. 10. The reaction vessel in claim 1 can be any vessel that is capable of being sealed such as a batch reactor or micro flow reactor that can hold an anaerobic or aerobic atmosphere. 1 1. The micro flow reactor in claim 10 can be a microreactor, flow reactor or flow apparatus bearing a design engineering functionality consisting of pre-fabricated channels and grooves with dimensions ranging from 1 micrometer to 200 micrometers. 12. The micro flow reactor in claim 10 can have the chemical reaction fluid passing inside the inner channels and grooves with distances travelled by the reaction fluid ranging from 1 mm to 1000 meters. 13. The reaction vessel in claim 1 and claim 10 is capable of obtaining temperature ranges from - 150°C to 1000°C. 14. The micro flow reactor in claim 10 is capable of altering and regulating the rate of reaction fluid flow and the residence times within the prefabricated channels or grooves. 15. The reaction fluid flow rate in claim 14 can be within the ranges of 0.000100 mL/minute- 500L/min. 16. The residence times in claim 1 can be within the ranges of 1.0 seconds- 1 OOh. 17. The chemical process of claim 1 can also use a solvent blend, amine solvent blend, oxidant, indene, and metal salt to form 1 ,2,3,4-tetrahydroisoquinolines using a reaction vessel comprising of the steps; a. Combining the indene and solvent blend for a specified period of time before, b. Adding the metal salt followed by the oxidant before, c. Removing the solvent and adding the amine solvent blend before, d. Cooling and adding the reducing agent. 18. The solvent blend in claim 1 and claim 17 can be water that contains an organic solvent. 19. The organic solvent in claim 6 and claim 18 can be tetrahydrofuran or methanol containing amine. 20. The amine solvent blend in claim 17 can contain methanol and acid and amine. 21. The amine in claim 19 and in claim 20 can be a substituted primary amine. 22. The oxidant in claim 17 and claim 1 can be a periodate oxidant containing an inert material. 23. The indene in claim 1 and claim 17 can be a phenyl and methyl substituted indene. 24. The metal salt in claim 17 can contain potassium osmate in catalytic and stoichiometric quantities. 25. The 1,2,3,4-tetrahydroisoquinolines made from the process in claim 1 and 17 are obtained in 0.5 hours. 26. The 1 ,2,3,4-tetrahydroisoquinolines made from the process in claim 1 and 17 are obtained in 12 hours. 27. The amine solvent blend in claim 17 and claim 20 contains two solvent mixtures where; a. Solvent 1 contains methanol and acid. b. Solvent 2 contains methanol and the amine. 28. The reaction vessel in claim 17 is the same as in claim 1 , claim 10, claim 1 1 , claim 12, claim 13, claim 14, claim 15, and claim 16. 29. The metal salt in claim 7 can contain potassium osmate in catalytic quantities. |
Invention #2 - Process to make highly substituted indenes using metal salt catalysts
Invention # 3 - The cross coupling of 2-bromo-l -phenyl indenes with phenyl acetylenes and other substituted acetylenes in water.
Table of Contents
Page
1.0 - Introduction 3
2.0 - Invention #la-lb - The synthesis of tetrahydro isoquinolines from 2-Methyl- 1 phenyl substituted indenes 4
2.1 - Novelty and Uniqueness of Invention 4
2.2 - Osmium 4
2.3 - Isoquinolines that Have Biological Activity 5
3.0 - Invention #2 - The synthesis of 2-bromo-l -phenyl indenes from the 1,2-biaryl gem- dihalocyclopropanes 6
3.1 - Novelty and Uniqueness of Invention 6
3.2 - Indenes 7
3.3 - Indenes that Have Biological Activity 7
4.0 - Invention # 3 - The cross coupling of 2-bromo-l -phenyl indenes with phenyl acetylenes and other substituted acetylenes in water 8
4.1 - Novelty and Uniqueness of Invention 8
4.2 - Alkynes 8
4.3 - Alkynes that Have Biological activity 9
5.0 - Pharmaceutical, and Generic Drug Manufacturing in Canada 9
5.1 - Potential Customers and Target Market 9
5.2 - Potential customers located in the greater Toronto area 9
6.0 - Use of a Device to Perform Chemical Processes 10
6.1 - Products and Companies that use Microreactor FlowTechnology 10
6.2 - Companies that use microreactors for their processes 1 1
7.0 - Conclusion 1 1 1.0 - Introduction
The following document contains some market research data concerning the recent invention disclosures. It outlines the uniqueness of each invention and some background information about the conditions, materials and compounds synthesized in the process in question. In addition relevant uses of the end products, current companies that are involved in the synthesis, sale, and manufacturing of the compounds are summarized. The following unique processes would be beneficial to customers because of the increase in efficiency, safety, and a decrease in waste by products.
2.0 - Invention #la-lb - The synthesis of tetrahydro isoquinolines from 2-Methyl- 1-phenyl substituted indenes
The use of osmium tetroxide in the oxidative cleavage of the indene double bond 1 to form the corresponding keto aldehyde product 45%-65% yield (Invention la). This keto aldehyde 2 is then used in the reductive amination protocol with primary amines to synthesize 2,3,4-substituted tetrahydroisoquinolines 3 in 28%-99% yields {Invention lb). (10 examples)
2.1 - Novelty and Uniqueness of Invention
1) The described process involves the synthesis of highly substituted isoquinolines (3) in high yields starting from the corresponding substituted indene (1). A process and/or protocol does not currently exist to make isoquinoline products with the substitution patterns present in the final isoquinoline.
2) The process involves the use of osmium tetroxide to cleave the indene double bond forming the keto aldehyde product (2) which is combined with the corresponding substituted amine forming the substituted isoquinoline.
3) A process does not exist to perform an oxidative cleavage on an indene scaffold using osmium.
2.2 - Osmium
Osmium is a very useful catalytic metal in synthesis because of the reactions that can be performed (i.e.- Oxidative cleavage, dihydroxylations, aminohydroxylations). These reactions are used by many pharmacuetical companies and companies that synthesize building blocks for pharma (i.e. -third party synthetic contractors). The only alternative to osmium to perform an oxidative cleavage reaction involves the use of ozone which is a toxic, explosive and a hazardous gas to use. An ozone generator is needed to generate ozone for the reaction, and the reactions are not selective giving rise to many unwanted side products which leads to an increase in waste production, and a decrease in reaction efficiency.
2.3— Isoquinolines Have Biological Activity
Have many medicinal properties that allow them to be useful products for the treatment of various medical conditions. The high biological activity that isoquinolines have allows them to be attractive targets for pharma companies. There are many isoquinoline products that currently exist to be used as viable treatments.
1) Vasodilators such as papaverine are isoquinolines that are currently used pharmaceuticals.
Sold under the brand names: Pavacap, Pavadil (USA), Artegodan, Panergon (Germany), Cardiospan, Papaversan (France), Cardioverina (Countries outside Europe and US).
2) Hypertension and congestive heart failure such as quinapril.
Sold under the brand name: Accupril (Pfizer).
3) Anesthetics such as dimethisoquin.
4) Antifungal agents.
3.0 - Invention #2 - Process to make highly substituted indenes using metal salt catalysts
The synthesis of 2-bromo-indenes (1-4) from the corresponding 1,2-biaryl gem- dihalocyclopropanes using silver tetrafluoroborate in 1,2-dichloroethane at 65 °C. The reaction involves a 2π disrotatory electrocyclic ring opening of the cyclopropyl group facilitated by the precipitation of silver bromide (AgBr) to form the 1,3 -substituted allyl cation intermediate which undergoes a 4π conrotatory electrocyclic ring closing reaction to form 2-bromo-l -phenyl substituted indenes.
Scheme 1 - The synthesis of 2-bromoindenes from gem-dihalocyclopropanes
1 2 3 4
Scheme 2 - Electrocyclization of Symmetric gem-dibromocyclopropanes to form Indenes
3.1 - Novelty and Uniqueness of Invention
1) Other processes and/or protocols do not exist to synthesize highly 1,2-substituted indenes involving the use of silver salts. Other methods involve the use of very strong acids which are very hazardous due to their corrosive nature or toxic metal catalysts.
2) The process involves an electrocyciization cascade mechanism which is a very efficient high yielding reaction and never used for the synthesis of indenes.
3) The final products are part of a chemical class of indenes which have been shown to possess many desirable medicinal properties (i.e. - anticancer, insulin modulators, cardiovascular, anti obesity). They have similar core structures as in the D vitamins.
3.2 - Indenes
1) Indenes are naturally occurring compounds isolated from coal tar fractions/crude oil refining.
2) Main uses of indenes are for the production of indene resin which is the starting point for many plastic products (i.e., floor tiles). Also used as thermal imaging material for stenciling.
3) Indenes have been shown to possess many desirable properties and are also biologically active used as pesticides imbedded in plastic animal collars.
4) Indenes are available pharmaceuticals for the treatment of HIV (Crixivan -Merck, $275 million/2008 annual revenue) and pain (Sulindac). .3 - Indenes that have biological activity:
1) Used for treatment of cerebral vascular disease - Indeloxazine (Japan).
2) Estrogen receptor agonists.
3) Selective modulators for the peroxisome proliferator activator receptor (PPAR).
4) Anti-inflammatory pharmaceutical agents - Sulindac - Clinoril - Merck US and UK.
5) Antifungal agents.
6) Used for treatment of precancerous and cancerous lesions.
7) Used as muscarinic agonists (Eli Lilly) (made via osmium catalysis)
8) Used as anticoagulants. 4.0 - Invention # 3 - The cross coupling of 2-bromo-l -phenyl indenes with phenyl acetylenes and other substituted acetylenes in water.
This invention entails the synthesis of various cross-coupled products (20-80% yield) from the reaction between 2-bromo- 1 -phenyl substituted indenes with phenyl acetylene or propargyl alcohol. The reaction takes place in water in the presence of palladium chloride, triphenyl phosphine and pyrrolidine as base at 120 °C.
4.1 - Novelty and Uniqueness of Invention
1) There has not been any process's and/or protocol's or examples that involves the cross- coupling between an alkyne and an indene.
2) Conventional synthetic protocols that involve coupling alkynes involve the use of organic and/or halogenated solvents which from a safety standpoint are very hazardous due to their explosive nature and toxicity (i.e., carcinogenic, tetratogenic). This process offers an alternative to the use of these solvents since the reaction is performed in water which is the safest and most environmentally friendly solvents.
3) Current processes need 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. By not having to use copper, this eliminates exposure concerns during process operation. In addition, the use of copper is expensive from an industrial perspective and by eliminating the need for copper eliminates the costs associated with its use.
4.2 -Alkynes
1) Alkynes are petroleum products for chemical feedstocks.
2) Alkynes are components of various rubbers and plastics.
3) Used as thermosetting resins and insulators.
4) There are alkynes that have biological activity and are used as pharmaceuticals.
5) They are primarily used as building blocks for other compounds. 4.3 - Alkynes that have biological activity:
1) Efaviren (Sustiva) HIV inhibitor pharmacuetical.
2) Terbinafine (Lamisil, Zimig) antifungal agent.
3) Esperamicin and calicheamicin are two of the most potent antitumor agents available.
5.0 - Pharmaceutical, and Generic Drug Manufacturing in Canada
Industry Government website statistics show that in Canada there are over 1 1 000 pharmacuetical, and chemical manufacturing companies operating and that 8000 reside in Ontario. The total revenues from this industrial sector were over $10 billion for 2009 and that imports of generic drugs and chemicals totaled over $5 billion in 2009. Ontario is a very good market to start with.
There are several companies that would use these processes to synthesize products that they use or sell:
la) Use of osmium for the oxidative cleavage of indenes.
lb) Process to synthesize isoquinolines.
2) Process to synthesize highly substituted indenes (feedstock chemicals for isoquinoline synthesis).
3) Process to cross-couple 2-bromo indenes with alkynes in water and without copper.
5.1 - Potential Customers and Target Market for the Invented Processes
The target market of the inventions would be:
1) Large pharmaceutical companies (i.e., Merck, Pfizer, Genentech, Eli Lilly,
GlaxoSmithKline).
2) Large chemical manufacturing companies (i.e., Dow Chemical, Corning, Exxon).
3) Generic drug manufacturers (i.e., Patheon, Apotex, Dalton).
4) Small pharma/chemical manufacturers and specialty chemicals (i.e., Catalent, TCI, TRC).
5) Government R D facilities.
6) University and small contract R/D companies.
- Potential customers located in the greater Toronto area.
1) Large pharmaceutical companies: Glaxo Smith Kline.
2) Large chemical manufacturing companies: Unilever.
3) Generic drug manufacturing companies: Patheon, Apotex.
4) Small chemical manufacturers and specialty chemicals: Toronto Research Chemicals (TRC)
5) University and small contract R/D companies: University of Toronto, Ryerson University, York University, McMaster University. 6.0 - Use of a device to perform the processes
A microreactor flow device that has the capability of performing the above processes would be very beneficial and advantageous for the customer for several reasons:
1) A device would allow for the handling and recycling of osmium helping to minimize costs associated with the purchasing, storage, usage, and disposal of osmium and its corresponding waste addressing many environmental concerns.
2) A device would minimize human exposure to osmium and the corresponding waste since it is contained in the device. This is a benefit for the customer since an added level of safety is achieved.
3) These microreactor flow devices have been shown to be more efficient than conventional batch synthesis by having the ability to increase in reaction efficiency by minimizing waste byproducts.
4) These microreactors have also been shown to allow chemical reactions to be completed in a faster time.
5) These devices are usually fully automated and controlled by a computer that allows for quick optimization of a reaction by allowing to change variables such as temperature, flow rate, concentration, and time.
6) The device is a small, compact, modular, reactor that has a chemical output that is constant (i.e., lg/lmin-l g/h). To achieve large scale production the devices are "numbered up" instead of "scaling up" (i.e., 1 device makes lg/min, therefore after 24h = 1.44 kg, after 365 days = 525.6 kg. If 50 devices were operational then 26.2 tons of product are achieved annually). Therefore due to the numbering up method, different synthetic procedures are not needed on the larger scale (i.e., typically a small batch scale synthesis (lg) differs from the large scale (1 ton) synthesis of the same product because different materials will be needed due to potential hazards and safety considerations associated with using a large amount of that chemical. Usually, pharma companies have a process scale up team that is aware of such hazards associated with these chemicals that specializes with large production of pharmaceuticals and chemical building blocks.). The microreactor device would not need a process scale-up team to implement large scale production of a drug or chemical.
8) The process allows for a large isoquinoline library and other similar products to be synthesized having the ability to access over 5 trillion isoquinoline products by varying the indene and amine starting materials.
9) The process can be used for the generation of new lead compounds, the manufacturing of generic drugs, chemical building blocks, and their scale up.
6.1 - Products and Companies that use Microreactor Flow Technology
There are several companies that are currently using flow microreactor systems. The H-Cube is a product sold by Thales-Nano. The H-Cube allows the user to carry out hydrogenations without the need for a hydrogen tank and can handle u to half a kilogram of material/day. The unit generates hydrogen via the electrolysis of water, collects the generated hydrogen, and uses it throughout the hydrogenation. The product has been shown to be very efficient giving better results than batch methods. In addition, the lack of a tank of hydrogen eliminates any explosive hazard which is a primary concern when carrying out hydrogenations. Further, the unit is computer interfaced allowing optimal conditions to be achieved automatically (i.e., temperature, flow rate, concentration, with respect to product yield). The H-Cube retails for about $60K US and has a new larger version that is capable of higher production volumes.
There are other companies that provide microreactor systems but they are not engineered for specific processes (i.e., a specific class of reaction like hydrogenations which the H-Cube is designed for.) but rather are available as a kit for the customer to use on their current chemistry and see if it adds a benefit to them.
6.2 - Companies that use microreaders for their processes
1) The top 20 largest pharmaceutical companies currently use microreactor technology to synthesize building blocks for pharmaceuticals (i.e., Merck, Pfizer, Genentech, etc.)
2) Lonza chemicals use microreactors for hydrogenations and dehydrations.
3) UOP and FMC use flow reactors for hydrogen peroxide synthesis.
4) Siemens- Axiva use microreactors for polyacrylamide synthesis.
5) Bayer-Schering use microreactors for DAST fluorinations (methods to incorporate fluorine into a molecule) and steroid synthesis.
6) Degussa chemicals use microreactors for chemical oxidations.
7) Xi'on Company (China) uses microreactors to synthesize nitroglycerine.
8) Merck uses microreactors for synthesis (Grignard reagents).
7.0 - Conclusion
The above inventions offer many uses and can bring value to customers because of their applicability in various chemical industries. They are unique and offer many advantages in terms of safety and efficiency. Patents on these inventions will help protect them and can aid in commercialization efforts.
PCT Application Background Information and Example Compounds
Indene synthesis and selected compounds (electrocyclization using catalysts)
Alkyne coupling and compounds Isoquinoline synthesis and compounds
Synthesis of highly substituted indenes and derivatives
Indenes and application
1) Indenes are naturally occurring compounds isolated from coal tar fractions/crude oil refining.
2) Main uses of indenes are for the production of indene resin which is the starting point for many plastic products (i.e., floor tiles). Also used as thermal imaging material for stenciling.
3) Indenes have been shown to possess many desirable properties and are also biologically active used as pesticides imbedded in plastic animal collars.
4) Indenes are available pharmaceuticals for the treatment of HTV (Crixivan -Merck, $275 million/2008 annual revenue) and pain (Sulindac).
Indenes that have biological activity
1) Used for treatment of cerebral vascular disease - Indeloxazine (Japan).
2) Estrogen receptor agonists.
3) Selective modulators for the peroxisome proliferator activator receptor (PPAR).
4) Anti-inflammatory pharmaceutical agents - Sulindac - Clinoril - Merck US and UK.
5) Agrochemical antifungal agents and produce coatings.
6) Used for treatment of precancerous and cancerous lesions.
7) Used as muscarinic agonists (Eli Lilly) (made via osmium catalysis)
8) Used as anticoagulants.
Alkynes
1) Alkynes are petroleum products for chemical feedstocks.
2) Alkynes are components of various rubbers and plastics.
3) Used as thermosetting resins and insulators.
4) There are alkynes that have biological activity and are used as pharmaceuticals.
5) They are primarily used as building blocks for other compounds.
Alkynes that have biological activity:
1 ) Efaviren (Sustiva) HTV inhibitor pharmacuetical.
2) Terbinafine (Lamisil, Zimig) antifungal agent.
3) Esperamicin and calicheamicin are two of the most potent antitumor agents available.
Isoquinolines and Application
Have many medicinal properties that allow them to be useful products for the treatment of various medical conditions. The high biological activity that isoquinolines have allows them to be attractive targets for pharma companies. There are many isoquinoline products that currently exist to be used as viable treatments.
1) Vasodilators such as papaverine are isoquinolines that are currently used pharmaceuticals. Sold under the brand names: Pavacap, Pavadil (USA), Artegodan, Panergon (Germany), Cardiospan, Papaversan (France), Cardioverina (Countries outside Europe and US).
2) Hypertension and congestive heart failure such as quinapril.
Sold under the brand name: Accupril (Pfizer).
3) Anesthetics such as dimethisoquin.
4) Broad spectrum microbicides
5) Phosphate free surfactants and detergents.