BATEY ROBERT A (CA)
| WO2008037604A1 | 2008-04-03 |
LIPSHUTZ ET AL.: "Sonogashira Couplings of Arrl Bromides: Room Temperature, Water Only, No Copper", ORG. LETT., vol. 10, no. 17, 7 August 2008 (2008-08-07), pages 3793 - 3796
LIANG ET AL.: "Copper-Free Sonogashira Coupling Reaction with PdCl, in Water under Aerobic Conditions", J. ORG. CHEM., vol. 70, no. 1, 24 November 2004 (2004-11-24), pages 1 - 393, ISSN: 0022-3263, Retrieved from the Internet
MERY ET AL.: "A very efficient, copper-free palladium catalyst for the Sonogashira reaction with aryl halides.", CHEM. COMMUN, vol. 15, 1 July 2003 (2003-07-01), pages 1934 - 1935, XP002320606, doi:10.1039/b305391c
| Claims 1 . A chem ical process that contains a solvent, palladium salt, alkyne, and indene in a vessel that may or may not be closed to form an alkyne coupled indene. 2. The palladium salt in claim I can be pallad ium chloride but is not lim ited to this specific palladium derivative and/or composition, 3. The alkyne in claim 1 can be phenylacetylene or propargyl alcohol but is not limited to these speci fic alkynes. 4. The indene in claim 1 is 2-bromo- l -phenyl indene and any other 2-bromo- l -phenyl substituted indene but not l imited to these indenes. 5. The solvent in claim 1 is water that contains a base in any amount that can be considered to have properties different from only water or only the base on its own. 6. The reaction vessel in claim 1 can be any vessel that is capable of being sealed but not limited to a vessel . 7. The reaction vessel in claim 1 can be a microreactor and/or flow apparatus bearing a design engineering functional ity consisting of pre-fabricated channels and/or grooves with dimensions ranging from I nanometer to 200 micrometers but not l imited to these dimensions. 8. The reaction vessel in claim 7 can have have the chemical reaction flu id passing inside the inner channels and/or grooves with d istances travel led by the reaction fluid ranging from I fm to 1 000 meters but not limited to these d imensions or combinations thereof. 9. The reaction vessel in claim 7 is capable of obtaining temperature ranges from - 1 50°C to 1000°C but not l imited to these temperature ranges. 10. The reaction vessel in claim 7 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 1 . The reaction fluid flow in claim 1 0 can be within the ranges of 0.000 1 mL/m inute-500L/min but not limited to these ranges. 1 2. The reaction flu id flow residence times in claim 1 0 can be within the ranges of 0.00001 seconds- 1 00 hours but not lim ited to these time ranges. 1 3. The reaction process i n claim 1 does not contain copper to regenerate the active palladium chemical entity needed for the reaction. 14. In claim 1 the reaction is performed in water. There has not been any chemical processes and/or examples that involves the cross-coupl ing between an alkyne or acetylene and 2- bromo- 1 -phenyl indene i n water. Th is process can cross couple alkyne and an 2-bromo- l - phenyl indene in water. 1 5. Coupl ing of indenes and acetylenes requires copper. This process in claim 1 does not require copper. 1 6. Coupl ing alkynes involves the use of petroleum, and/or halogenated solvents that can be dangerous due to their flammabil ity, and/or toxicity, and/or environmental problems but not limited to. This process does not use toxic and/or flammable solvents that pose an environmental hazard. This process uses water as a solvent to form 2-alkynyl- l -phenyl indenes which eliminates and/or minimizes these concerns 17. 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 in claim 1 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. |
| AMENDED CLAIMS received by the International Bureau on 27 January 2014 (27.01 .14) 1. A chemical process that contains a base solvent blend, palladium salt, triphenylphosphine, alkyne, and a substituted indene in a vessel such as a batch or flow micro reactor that can be sealed to form an alkyne coupled indene without the use of copper or other additives in an atmosphere that can be aerobic or anaerobic. 2. The palladium salt in claim 1 is palladium chloride. 3. The alkyne in claim 1 can be any alkyne such as phenylacetylene or propargyl alcohol which does not contain a pyridine group. 4. The indene in claim 1 can be a bromo and phenyl substituted indene such as 2-bromo-l - phenyl indene which is not used as a monomer. 5. The base solvent blend in claim 1 can be water that contains a base in any amount that can be considered to have properties different from only water or only base on its own and does not need the addition of additives. 6. The reaction vessel in claim 1 can be a vessel that is capable of being sealed. 7. The reaction vessel in claim 1 can be a microreactor and/or flow apparatus bearing a design engineering functionality consisting of pre-fabricated channels and/or grooves with dimensions ranging from 1 nanometer to 200 micrometers. 8. The reaction vessel in claim 7 can have the chemical reaction fluid passing inside the inner channels and/or grooves with distances travelled by the reaction fluid ranging from 1 mm to 1000 meters. 9. The reaction vessel in claim 7 is capable of obtaining temperature ranges from -150°C to 1000°C. 10. The reaction vessel in claim 7 is capable of altering and/or regulating the rate of reaction fluid flow and the residence times within the prefabricated channels and/or grooves. 11. The reaction fluid flow in claim 10 can be within the ranges of 0.000 lmL/minute-500L/min. 12. The reaction fluid flow residence times in claim 10 can be within the ranges of 0.00001 seconds-100 hours. 13. The reaction process in claim 1 does not contain additives such as copper and/or micelle forming compounds to regenerate the active palladium chemical needed for the reaction. 14. The base solvent blend of the process in claim 1 can be water which is used in a flow reactor for added process safety and efficiency. 15. The process in claim 1 does not use copper as a co-catalyst in the batch vessel and/or flow reactor which minimizes the formation of waste products. 16. The process in claim 1 can use a base solvent blend containing water that can contain a base providing a solvent without explosion and flammability hazards and can be used with a microreactor or flow reactor as the solvent which can further minimize explosion risks providing an increase in safety. 17. The process described in claim 1 is an environmentally friendlier and greener process than other alkyne coupling methods to make indene coupled alkynes because the base solvent blend can be water which is not toxic and carcinogenic or pose an environmental concern because a microreactor or flow reactor can be used. 18. The process in claim 1 can make an indene and alkyne containing molecule of the structure I as shown in drawing 1 that is not used as a monomer. 19. A chemical process that contains a solvent, palladium salt blend, alkyne or propargyl containing chemical* a base, and an indene in a batch reactor or a flow reactor that can be sealed to form an alkyne coupled indene without the use of copper or other additives in an atmosphere that can be aerobic or anaerobic where the said process comprises the steps; a) Pre stirring the indene and alkyne for a specified period of time before, b) Adding the palladium blend before. c) Adding the water and base before, d) Heating the reaction mixture for a specified period of time. 20. The palladium salt blend in claim 19 can contain triphenylphosphine. 21. The solvent in claim 14, claim 16 and claim 19 can be water or water containing a base. 22. The base in claim 16 and claim 19 can be pyrrolidine or pyridine. 23. The base in claim 16 and claim 19 can be pyrrolidine containing water in any amount. 24. The base in claim 16 and claim 19 can be pyridine containing water in any amount. 25. The propargyl containing chemical in claim 19 can be a propargyl alcohol. |
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- 1 -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- 1 -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 FiowTechnology 10
6.2 - Companies that use microreactors for their processes 1 1
7.0 - Conclusion 11 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 Ma-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 animation 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
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-hromo-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. - 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 11 000 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.
5.2 - 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-lg/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 up 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 microreactors 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 fiuorinations (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 refin
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 ai 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).
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.
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