MXPA98004284A - Process used by multip stake reactors - Google Patents
Process used by multip stake reactorsInfo
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- MXPA98004284A MXPA98004284A MXPA/A/1998/004284A MX9804284A MXPA98004284A MX PA98004284 A MXPA98004284 A MX PA98004284A MX 9804284 A MX9804284 A MX 9804284A MX PA98004284 A MXPA98004284 A MX PA98004284A
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- ligand
- carbon monoxide
- organophosphorus
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Abstract
This invention relates to a process for the production of one or several products in a multi-stage reactor having more than one reaction stage where the process comprises the reaction in said multi-stage reactor of one or several reagents with carbon monoxide in the presence of a metal-organophosphorus ligand catalyst and optionally free organophosphorus ligand to produce said product or said products, wherein said metal-organophosphorus ligand catalyst is not subjected to a substantial deactivation in the presence of only carbon monoxide and / or effect a normal product selectivity change of less than 0.2% of the normal product under a carbon monoxide partial pressure of 1 pound per square inch and / or effect change in the reaction rate of less than 2% under one partial pressure of carbon monoxide of 1 pound per square inch
Description
PROCESSES USING MULTIPLE STAGE REACTORS Brief Summary of the Invention TECHNICAL FIELD This invention relates to some processes catalyzed by arganic phosphorus metal complexes, such as, for example, carbonylation and hydroformylation, which can be carried out in a stage reactor. multiple Background of the Invention The r €? Continuously stirred tank reactor vessels (CSTRD convention used in chemical processes provide only one theoretical reactive stage per vessel.) When the objective is to bring a reaction to its completion and the magnitude of the conversion is not limited by the equilibrium, it is helpful to employ Several reaction steps in series Otherwise, the evaluated reagent must be recovered and recycled through the reaction system Normally, a reaction to its completion in a single passage through the system is achieved by placing several stirred tank reactors with only one It would be desirable to carry out processes in reactors designed with multiple stages that create more than one theoretical reaction stage per vessel.A disadvantage of carrying out processes that employ carbon monoxide in a multi-stage reactor is that the selectivity of normal product using catalysts from
The rhodium-tri-phenyl-1-phosphine complex presents a significant response to the change in partial pressure of carbon monoxide and / or the total regimen and the reaction shows a significant response to changes in the partial pressure of mono- carbon. Likewise, the rhodium-tripheni complex Ifosf ina catalysts are deactivated in the presence of carbon monoxide and hydrogen alone (in the absence of olefins). It would be desirable in the art to have a successful method to carry out the process employing carbon monoxide in a layered reactor. Presentation of the invention It has been found that some processes catalyzed by organophosphorus metal-ligand compounds, for example, carbonylation and hydroformylation, wherein the organophosphorus met l-ligand complex catalyst does not exhibit a substantial deacivation in the presence of monomers. The only carbon or carbon monoxide and hydrogen alone and / or where the normal product selectivity does not have a significant response to the partial pressure change of carbon atom and / or where the reaction does not exhibit a Significant response to the changing carbon monoxide partial pressure can be carried out in a multi-stage reactor. Thus, this invention improves economic characteristics of the processes catalyzed by
metal-ligand complex of organo-phosphorus that employ carbon monoxide by eliminating the need for separate multiple reactors and the higher capital costs associated with that need. This invention relates in part to a process for producing one or more products in a multi-stage reactor having more than one reactive stage, said process comprising the reaction in said multi-stage reactor of one or more reactors with carbon monoxide. in the presence of a metal-organophosphorus ligand catalyst and optionally free organophosphorus ligand to produce said product or said products, wherein said metal-organophosphorus ligand catalyst is not subject to an ion deactivation. Substantially in the presence of carbon monoxide only and / or effect a change in the normal selectivity of the product from less than 0.2% of the normal product to 1 pound per square inch of partial pressure of carbon monoxide. This invention also relates in part to a hydroformylation process for producing one or more aldehydes in a multi-stage reactor having more than one reaction step, said process comprises reacting said reactor in stages of one or more alefious unsaturated compounds with carbon monoxide and hydrogen in the presence of an organophos gold metal-ligand catalyst
and optionally free organophosphorus ligand to produce said aldehyde or said aldehydes, wherein said organophosphorus meta-1 complexing catalyst is not subject to a substantial deactivation in the preseof only carbon monoxide and hydrogen and / or effect a change in as to selectivity of aldehyde less than 0.2% of normal aldehyde per 1 pound per square inch of partial pressure of carbon monoxide. This invention also relates in part to a process for producing one or more products in a reactor in stages that has more than one reactive stage, said process comprises the reaction in said reactor in stages of one or several reagents with carbon monoxide in the preseof of an orgapofosphorus metal-ligand catalyst catalyst and optionally free organophosphorus ligands to produce said product or said products, wherein said metal-organophosphorus ligand catalyst is not subjected to a substantial deactivation in the preseof only monoxide of carbon and / or effect a change in normal product selectivity of less than 0.2% of normal product per 1 pound per square inch of partial pressure of carbon monoxide and / or effect a change in reaction rate of less than 2% per 1 pound per inch block of partial pressure of carbon monoxide. This invention also relates in part to a process of
hydroformylation to produce one or more aldehydes in a reactor in stages having more than one reaction stage, said process comprises the reaction in said reactor in the stage of one or several unsaturated olefinic compounds with carbon monoxide and hydrogen in the preseof a metal-organophosphorus ligand catalyst and optionally free organophosphorus ligand for producing said aldehyde or said aldehydes wherein said metal-organophosphorus ligand complex catalyst is not subjected to a substantial deactivation in the preseof only carbon monoxide and hydrogen and / or make a change in normal aldehyde selectivity of less than 0.2% normal aldehyde per 1 pound per square inch of partial pressure of carbon monoxide and / or effect a change in the reaction rate of less than 2% by 1 pound per square inch of partial pressure of carbon monoxide. DETAILED DESCRIPTION In addition to the advantages of high raw material conversion / or reduced total reactor volume resulting from the use of multi-stage reactors in the processes of the invention, further advantages of this invention include, for example, a reduced consumption of the valuable catalyst of metal-organophosphorus ligand complexes due to the smaller total reactor volume, to a formation
Reduced heavy by-products due to a smaller volume of total reactor, the elimination of expensive and complicated equipment for the recovery of defines and recycling equipment due to the high conversion, and the ability to use less pure feed products directly and efficient. The multi-stage reactor useful in this invention preferably comprises an elongated reactor vessel positioned substantially vertically, containing at least one, preferably two or more, introduction devices, and at least one, preferably two or more output devices. . The input devices may be located in the bottom part of the reactor vessel and the output devices may be in the upper portion of the reactor vessel. The reagents are continuously introduced into the input device and the products and reagents that did not react are continuously removed through the output devices. A mixing device, an agitator, with several blades is placed inside the reactor and extends substantially throughout the entire length of the reactor. In addition, the inner wall surface of the reactor is preferably equipped with several deflection devices that fit between the stirrer blade. The reactor vessel can also be equipped with a removal device
of heat, for example, a heat exchanger or internal cooling coils, in order to keep the reactants at the desired reaction temperature. The reactor can have a generally elongated shape, for example, a tube, preferably a cylindrical shape, whose overall volume depends on the desired production and the product to be synthesized in the reactor. The relationship between the length of the reactor and its diameter is not a strictly critical factor and is determined by the number of reaction zones it contains. The reagents can be introduced into the reactor vessel through the input devices in the lower portion and upper portion of the reactor vessel. For hydroformylation, illustrative reagent entry devices in the lower portion of the reactor vessel include: < i > a first reagent input device for continuously transporting one or more catalysts and optionally one or more olefinic compounds in the reactor device} and < ii) a second reagent input device for transporting continuously a source of hydrogen and carbon dioxide and optionally one or more olefinic compounds in the reactor device. The first reagent input device can be placed on the same side as the reactor device or on the opposite side as the second
Reagent input device. A third reagent input device for continuously transporting one or more olefinic compounds in the reactor device can be used preferably in the case where the olefinic compound (s) is not transported by the first or second reagent input device. Reagent input devices in the upper part of the reactor device preferably comprise one or more reagent input devices for continuously transporting one or more olefinic compounds, one or more catalysts and / or a source of hydrogen and carbon monoxide in the reactor device, preferably carrying a source of hydrogen and a monomer of carbon in said reactor device. In one embodiment, the reactor is positioned substantially independently. The term "substantially vertical entity" as used herein refers to the pass-through of the reactor which allows the gases to advance upwards. Thus, the reactor can be placed in > 0 ° to 90"in relation to the horizontal A stirring device, comprising an elongated rod, extending the entire length of the reactor and having several blades can be placed inside the reactor vessel in such a way as to extend the all throughout the reactor, thus ensuring a mixture
efficient and uniform hydroformylation reagents. The rod with the alternating blades is rotated continuously by a conventional motor device, preferably placed outside the reagent vessel, during the course of the reaction. Furthermore, the inner surface of the reactant vessel preferably contains several deviators positioned generally horizontally or inclined at an angle similar to the angle of the shaker blades and spaced at said intervals such that they fit between the agitator. The combination of diverters and rotating stirrer blades provide sufficient turbulence for reagents to ensure adequate contact for the reactions to take place. Unreacted products and reagents can be recovered from the reaction vessel at the top of the reactor in a product collection device or either transferred to a product separation device or a subsequent reactor in series via a duct optionally Equipped with a valve device. One of the purposes of the valve is to allow the isolation of the reactor vessel in relation to the product collection device or product separation device or next reactor in series. The output devices of the product in the portion
The top of the reactor device preferably comprises: (i) a first product outlet device for continuously removing product and catalyst and unreacted reactants from the reactor device; and (ii) a second product outlet device for continuously removing product and unreacted reagents from the reactor device. The composite parts of a multi-stage reactor that can be constructed from any commonly used building material that is inert in relation to the reactants and products. Accordingly, the reactor vessel can be made of high grade stainless steel, with internal walls of the reactor being placed to avoid deposits therein. The agitation of the reactor can also be made of stainless steel with blades welded or screwed there, or the blades and the agitator can be made in the form of a unitary block material, for example metal casting. See, for example, U.S. Patent Nos. 3,194,638, 3,222,141, 3,266,872, 3,950,138, 4,374,093, 4,483,624, 5,073,311, 5,098,669, T 986,030, 1,338,698, 2,192,124, 2,582,899, 2,590,436, 3,909,207, and 4,996,029, whose ions are incorporated herein by reference . See also, for example, Fasano, Julian B., W. Ray Penney, and Bang Cheng Xu; "Design and Scale of Comply, Staged Process Equipment with
E phasis an Interstage Back i? Ing, "(Design and Increase of Process Equipment in Stage, Compartmentalized, with Emphasis in the Retro ezcla between Stages), Presentation given in the 14th Bi-Annual Conference of mixtures of the Engineering Foundation, in Santa Barbara, CA, from June 20 to 24, 1993, Prengle, H. William, Jr., and Narses Barona, "Make Petrochemical by Liquid Phase Oxidation: Part 2: Kipetics, Maßs Tranßfer and Reactor Design," ( Elaboration of Petrochemicals by Liquid Phase Oxidation: Part 2: Kinetics, Mass Transfer and Reactor Design), Hyd ac rbon Processing, Not December 1970, pages 159-175, and Oldshue, JY, and JH Rushton, "Continuous Extraction in a Multistage Mixer Column, "(Continuous Extraction in a Multi-Stage Mixer Column), Chemical Engineering Progress, Vol. 48, June 1952, pages 297-306, the presentations of which are incorporated herein by reference. the multi-stage reactor useful and This invention comprises a container adapted to contain a carbonylation ion or hydroformylation reaction. The inner part of the container can be divided into several chambers of the same size or different sizes by means of generally horizontal deviatextending inward from the inner wall of the container. Each deviator has a hole generally in its central part and each hole is aligned with each of the
MX 9804365A Batch: N980C136
Date: 1/18/1999
Number of pages: 78
Previous document: MX 9804284A
ext document: MX 9804366A
PCT WORLD INT? LLECTUAL PROPERTY ORGANIZATION International Burcau
I TERNA? ONAL APPUCATION PUBLISHED UNDER THE PATENT COOPERA? ON TREATY (PCT)
(51) International Patent Classification 6: (11) International Publication Number: WO 98? 4447
C07D 471 04, A6 K 31 435, C07D Al 487 04 // (C07D 471 04, 221: 00, 209: 00) (43) International Publication Date: 9 April 1998 (09.04.98) (C07D 48704, 209: 00 , 209: 00) (C07D 48704, 223: 00, 209: 00) (21) International Application Number: PCT / DK97 / 00418 (81) Despegnated States: AM, AT, AU, BB, BG, BR, BY, CA , CH, CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HU, IS, JP, KE,
(22) International FUing Date: 1 October 1997 (01.10.97) KG, KP. KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TT, UA, UG, US, UZ, VN, ARIPO patent (GH,
(30) Priority Data: KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
1069/96 1 October 1996 (01.10.96) DK BY, KG, KZ, MD, UK, TJ, TM), European patent (AT, BE, 1277/96 13 November 1996 (13.11.96) DK CH, DE, DK, ES, Fl, FR, GB, GR, LE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, Cl, CM, GA, GN, ML, MR, NE, SN, TD, TG). (71) Applicant (for all designated States except US): NEU- ROSEARCH A / S (DK DK); Smedeland 26B, DK-2600 Glostrup (DK). Publisbed With international search report. (72) Inventors; and (75) Inventors Applicants (for US onfy): ÁTJEN, Frank [DK DK]; NeuroSearch a / s, Smedeland 26 B, DK-2600 Glostrup (DK). DREIER, Jßrgen [DK / DK]; NeuroSearch a / s, Smedeland 26 B, DK-2600 Glostrup (DK). (74) Common Represen tive: NEUROSEARCH A S; Smedeland 26 B, DK-2600 Glostrup (DK).
(54) T? Tle: NOVEL INDOLE-2.3-DIONE-3-OXIME DERIVATIVES
(57) Abstrae! The present invention relates to novel indole-2,3-dione-3-oxime derivatives of antagonizing the effect of excitatory amino acids, such as glutamate. More specifically the novel indole-2,3-dione-3-oxime derivatives of the invention may be described by general formula (I), wherein R3 represents "Het", or a group of formula (II), wherein '? Ef represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, at least one of R31, R32, and R33 independently represents hydrogen, alkyl, or hydroxyalkyl, and at least one of R31, R32, and R33 independently represents (CH2) nRM; wherein R34 represents hydroxy, carboxy, alkoxycatbonyl, alkenyloxycarbonyl, alkynyloxycatbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbony], aralkoxycarbonyl, CONR ^ R36, or '? et "; wherein n is 0, 1, 2, or 3; and R5 represents phenyl , naphthyl, thienyl, or pyridyl, all of which may be substituted. "A" represents a ring of five atoms with the benzo ring at the positions marked "a" and "b", and formed by the following bivalent radicals : a-NR6-CH2-CH2-b; a-CH? -NR6-CH2-b; a-CH2-CH2-NR6-b; a-NR "-CH2-CH2-CH2-b; a-CH_-NR6 -CH2-CH2-b; a-CHi-CTft-NR'-CH? -b; a-CH2-CH2-CH2-NR6-b; a-NR6-CH2-CH2-CH2-CH2-b; -NR6-CH2-CH2-CH2-b; a-CH2-CH2-NR1'-CH2-CH2-b; a-Of-Ofc-CHi-NRβ-CH? -b; or a -CH2-CH2-CH2- CH2-NR6-b wherein R6 represents hydrogen, alkyl or CH2CH2OH; or a pharmaceutically acceptable salt thereof.
NOVEDOUS DERIVATIVES OF IIMD0L0-Z, 3-DI0N0-3-0XIMA
AJ SPENT S FOR THE IRVEHCSON
The present invention relates to novel indolo-2,3-di-o-3-a derivatives capable of antagonizing the effect of excitatory amino acids such as glutamate. The invention also relates to a method for preparing the chemical compounds of the invention, the pharmaceutical compositions comprising the chemical compounds and a method of treatment therewith.
ANTEGENENT S PE? ? ? M? qN
Excessive excitation by neurotransmitters can cause degeneration and death of neurons. It is believed that this degeneration is partly mediated by the excitotoxic actions of the excitatory amino acids (EAA). glutamate and aspartate »in N-methyl 1-D-aspartate (NMDA). the receptor for alpha-ami o-3-hydroxy-5-methyl-1-4-isoxazole propionic acid (AMPA) and the receptor of cainata. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a variety of conditions. such as thromboembolic or hemorrhagic stroke »cerebral vasospasm. hypoglycemia ia »cardiac arrest. state of evil
epileptic, perinatal asphyxia. anoxia such as semi-choking »lung surgery and brain trauma as well as lathyrism. Alzheimer's and Huntington's diseases. Therefore, compounds capable of blocking the excitatory amino acid receptors are considered useful for the treatment of the above disorders and diseases, as well as amyotrophic lateral sclerosis (ALS). schizophrenia, bad ParK nson. epilepsy, anxiety »pain and drug addiction.
BUE E PESCRI iQN PE U? INVENTION
It is an object of the present invention to provide novel derivatives of indolo-2,3-dione-3-oxy which are excitatory amino acid antagonists and are useful in the treatment of disorders or diseases of mammals, including humans »that respond to antagonists of the excitatory amino acid receptor. Accordingly, in this first aspect, the invention provides the novel ndolo-2'-3-dione-3-oxime derivatives described in claim 1. In another aspect the invention relates to the use of a chemical compound of the invention for the preparation of a pharmaceutical composition. In a third aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the chemical compound of the invention
together with an excipient, pharmaceutically acceptable carrier or diluent. In a fourth aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal "including a human, whose disorder or disease responds to receptor antagonists. of glutamic acid and / or aspartic acid. In a more specific aspect, the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of cerebrovascular disorders. lathyrism. Alzheimer disease. Huntington's diseases. Amyotrophic lateral sclerosis (ALS) »schizophrenia» Parkinson's disease »ep lepsy, anxiety» pain or drug addiction. In a fifth aspect the invention provides a method for treating disorders or diseases of living animals "including humans" that respond to the excitatory amino acid receptor antagonists "which comprises administering to the body of a living animal" including a human being, which needs of the same an effective amount of a chemical compound of the expiration. In a more specific aspect the invention provides a method for treating a cerebrovascular disorder »lathyrism. Alzheimer's disease »Huntington's disease» Amyotrophic lateral sclerosis (ALS) »schizophrenia, Parkinson's disease.
epilepsy »anxiety, pain or drug addiction. In a sixth aspect the invention relates to the use of the chemical compound of the invention in a method for treating a disorder or disease of a mammal »including a human» whose disorder or disease responds to glutamic and / or aspartic acid receptor antagonists. »Said method comprising administering to the body of a living animal» including a human being, in need of an effective amount of the chemical compound. In a more specific aspect the invention relates to the use of the chemical compound of the invention in a method for treating a cerebrovascular disorder. lathyrism. disease
Alzheimer's »Huntington's diseases. Amyotrophic lateral sclerosis (ALS). schizophrenia, Parkinson's disease »epilepsy. anxiety, pain or drug addiction. In a seventh aspect of the invention provides a method for preparing a chemical compound of the invention. Further further objects of the present invention will be apparent to the person skilled in the art.
PESCf P? TQN PETALIAPA PE LA INYENGIPN Derivatives of Indo1o-2 > 3-diono ~ 3 ~ or ima
In this first aspect, the present invention provides novel indolo-2,3-d ono-3-oxime derivatives. The novel indolo-2 »3-dione-3-o? Ima derivatives can be described by
medium of the general formula (I)
where RJ. represents hydrogen »alkyl or benc lo» R »represents" Het "" or a group of the following formula
R31
wherein "Het" represents a saturated or unsaturated "monocyclic 4 to 7 membered heterocyclic ring" which optionally can be replaced one or more times by substituents selected from the group consisting of halogen, "alkyl, alkoxy and oxo" and therefore less one of Ra, R3 * and RM independently represents hydrogen, alkyl or hydroxyalkyl, and at least one of R3; R3se and R33 independently represents (CHae) r, Ra * where R ** represents hydroxy »carboxy» alkoxycarboni the"
alken loxicarboni lo, alkyloxycarboni lo. cycloalkoxy-carbonium »cycloalkyl-1-alkoxycarbonyl lo. aryloxycarbonyl. ara! coxi carboni lo. CONR3ßR3 * "or" Het "wherein R3ß and R3β represents hydrogen, alkyl, alkenyl. alkynyl. hydroxyalkyl. cycloalkyl "aryl" aralkyl or (CHβ) "- R3" 'where f 7 represents hydroxy carboxy, alkoxycarbon, alkeny loxycarbon, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl 1-alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbon or RJB and R3 * together with the N atom to which they are attached form a saturated 5 to 6 membered heterocyclic ring, optionally containing an additional N or O atom "and" Het "is as defined above, and n is O 1, 2 or 3, and Rβ represents phenyl, naphthyl, thienyl or pyridyl, all of which can be substituted one or more times with substituents selected from the group consisting of halogen CFa.Na, amino, alkyl, alkoxy, phenyl and SOaNRBXRßae, wherein Rßi and Rßa each represent hydrogen or alkyl, or S and Rβa together with the IM atom to which they are attached form a saturated 4- to 7-membered heterocyclic ring, optionally containing one IM atom or Or additional, and "A" represent to a ring of five to seven atoms
fused with the benzo ring in the positions marked "a" and "b". and formed by the following bivalent radicals: a-NR * -CHa-CHa-b; a-CH ^ -NR ^ -CHa- »a-CH3e-CH: e-NR« -b; a-NRβ-CHaí-CHa-CHβst-b; α-CH¡-NR * -CHSB-CHa-b; a-CHa-CHa-NR * -CHa-; a-CHsr-CH5B-CHss-NR «-;
a-CHat-NR "-CHSIf-CHas-CHa-b; a-CHa-CHa-? MR * -CHa-CHa-b; a-CHa-CHa-CHa-NR ^ -CHa-! O a-CHa- CHa-CHa-CHa-iMRβ-b "wherein R" represents hydrogen "alkyl or CHaCHaOH; or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the novel idol-2-3-dione-3-a derivatives can be described by means of the general formula (VI):
and where m is l. 2, 3 or 4. and In another preferred modality »the novel derivatives
8
of ndolo-2.3-dione-3-ima can be described by means of the general formula (II):
wherein R x represents hydrogen, alkyl or benzyl; "Het" represents a heterocyclic ring. onocicyclic. from 4 to 7 members saturated or unsaturated. whose ring can optionally be replaced one or more times by substituents selected from the group consisting of halogen, alkyl, alkoxy and oxo; n is O. 1. 2 or 3; β represents phenyl. naphthyl. thienyl or pyridyl. all of which can be replaced one or more times by substituents selected from the group consisting of halogen. CF3. N0a »amino» alkyl »alkoxy» phenyl and S0aN ßa-RBa; wherein ßx and Rßa each independently represent hydrogen or alkyl "or Rβa. and Rßa together with the N atom to which they are attached form a saturated 4 to 7-membered heterocyclic »mono-clc» ring, optionally containing an additional N or O atom; Y
"A" represents a ring of five to seven atoms fused to the benzo ring at the positions marked "a" and "b". and formed by the following bivalent radicals: a-NR * -CHa-CHa-b; a-CHa-NR * -CHa-; a-CH "-CH" -NR * -b;
a-CHa-NR - »- CHa-CHs a-CHa-CHs -NR * -CH» -b; a-CH, -CH, -CH, -NR * -; α-IMR * -CH, -CH, -CH, -CH, -b; a-CHa-R * -CHa-CHa-CHa-b i a -CHa-CHa-NR "-CHa-CHa-b; a-CHa-CHa-CHa-NR * -CHa-b O a-CHa-CHa-CHa-CHa-Rβ-b; wherein R * represents hydrogen, alkyl or CHaCHz0H. In a more preferred mode. the novel dolo-2'-3-dione-3-o? ima derivatives can be described by means of the general formula (II), above »wherein n is O. 1 or 2» and ß represents phenyl or pyridyl, of which both can be substituted one or more times with selected sub-elements from the group consisting of hal »CF3, N0Í ?, amino. alkyl, alkoxy, phenyl and SOalMRβa-Rßae "wherein Rβx and Rßa each independently represent hydrogen or alkyl" or
Rßa. already together with the N atom to which they are attached form a chain - (CH ^) ", - 5 where tn is 2» 3 »4» 5 or 6. In another preferred mode, the novel derivatives of ndolo-2.3- d ono-3-o? can be described by means of the general formula (III):
where R. Rß. R *. "Het" and n are as defined above. In yet another embodiment, the novel indolo-2,3-dione-3-oxime derivatives can be described by means of formula (II). wherein "Het" is a lactone of the general formula (VII):
where p is 1. 2. 3 or 4. In another preferred embodiment, the novel derivatives
eleven
of dolo-2,3-d? ono-3-o? a can be described by means of the general formula (IV):
wherein R x represents hydrogen, alkyl or benzyl; at least one of R33- »R33 and R33 independently represents hydrogen, alkyl or hydroalkyl, and at least one of R3: L, R3af and R33 independently represents (CHai)" R3 ^, wherein R3"4 represents hydro Carboxy, alkoxycarbonyl, alkeny loxycarbonyl, alkyne locarboxyl, cycloalkoxycarbonyl, cycloalkyl 1-alkocarbonyl, aryloxycarbonyl, alkoxycarbonyl, or C0.NR3ßR3β; wherein ae and e represent hydrogen, alkyl, alkenyl. alkynyl. hydroxyalqu. cycloalkyl. aril. aralkyl or (CHa "R3" - *. wherein R3"7 represents hydro? i.carbo? i, alkoxycarbonyl, alkeni loxycarboni, alkylo locarbon, cycloalkoxycarbonyl, cycloalkl-alkoxycarbonyl, aryloxycarbonyl. carboni lo; or ae and ae together with the N atom to which they are attached
12
form a saturated 5- to 5-membered heterocyclic ring which optionally contains an additional IM or O atom; and it is O, 1 »2 or 3; or one of R3 »R3S * and R33 represents hydrogen or alkyl» and two of R34- »R3Sβ and R33 together form a lactose ring of the general formula (VI):
where is l »2 or 3; and B represents phenyl »naphthyl» thienyl or pyridyl. all of which can be substituted one or more times with substituents selected from the group consisting of halogen CF3 »N0a» amino »alkyl» alco? i »phen lo and SOaNR? Rßae» where ßa. and ez each represents hydrogen or alk; or
Rßa. and RBS together with the N atom to which they are attached form a "monocyclic saturated 4 to 7 membered heterocyclic ring" which optionally contains an additional ÍM or 0 atom "and" A "represents a ring of five to seven atoms fused to the Benzo ring in the positions marked "a" and "b" »and formed by the following bivalent radicals: a-NR * -CH _CH _ •
13
a-CHa-NR-CHa-; a-CHa-CHa-WRβ-S a-NRβ-CHa-CHa-CHa-b; a-CHa-NR * -CHa-CHa-i a -CHa-CHa-NR "-CHa-b a-CHa-CHa-CHa-NR * -b; a ~ NR - "- CHa-CHa-CHa-CHa-b a-CHa-IM * -CHa-CHa-Ha-; a-CHa-CHa-IMR * -CHa-CHa-; a-CHa-CHa-Ha-NR * -CHa-; O a-CHa-CHa-CHa-CHa-lMR * -; wherein R * represents hydrogen, alkyl or CHa HaOH; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the novel indolo-2-3-d-o-3-o-ma derivatives can be described by means of the general formula (V):
where R3-. R3i. R3 *, R33, Rβ and R * are defined by the formula (IV) above.
14
Definition of Subßt tuven es
In the context of this invention, alkyl denotes a straight chain or a branched chain of one to six carbon atoms (C 1 -C 6 alkyl). which includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. in a preferred embodiment of this invention alkyl represents C 1 -C 4 alkyl, preferably C 1 alkyl, more preferably methyl, ethyl propyl or isopropyl. In the context of this invention cycloalkyl designates a cyclic alkyl containing from three to seven carbon atoms (cycloalkyl C? -C-), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the context of this invention alkenyl designates a group containing from two to six carbon atoms (alkenyl Ca-β) "including at least one double bond" for example but not limited to ethynyl, 1,2- or 2,3-propenyl. 1,2- or 3,4-buteni lo. In the context of this invention alkynyl designates a group containing from two to six carbon atoms (alkynyl Ca-Cβ) "including at least one triple bond, for example but not limited to ethynyl. 1.2- or 2 »3-propini lo» 1.2-. 2.3-or 3.4-butini lo. In the context of these invention cycloalkyl-alkyl designates a cycloalkyl as defined above which
fifteen
it is attached to an alkyl as defined above »v.gr.» ciclopropi Imeti lo. In the context of this invention aryl designates an aromatic hydrocarbon such as phenyl or naphthyl. In the context of this invention aralkyl designates an aryl as defined above which is attached to an alkyl as defined above. V.gr .. benzyl. In the context of this invention alkoxy designates an alkyl-O- where alkyl is as defined above. In the context of this invention, alkocarbonyl designates an alkyl-0-CO- wherein alkyl is as defined above. In the context of this invention cycloalco? carbonyl designates a cycloalkyl-O-CO- wherein cycloalkyl is as defined above. In the context of this invention cycloalkyl-1-alkoxycarbonyl designates a cycloalkyl 1 -alkyl- = -C0 wherein cycloalkyl 1 -alkyl is as defined above. In the context of this invention alqueni lo? I carboni designates an alken l-O-CO- where alkenyl is as defined above. In the context of this invention, alkyloxycarbonyl designates it as a -O-CO- wherein alkynyl is as defined above. In the context of this invention arylocarbonyl designates an aryl-O-CO wherein aryl is as defined
16
previously. In the context of this invention ara! co? i carboni designates ara1 qui l-O-CO- where aralkyl is as defined above. In the context of this invention halogen represents fluorine, chlorine, bromine and iodine. In the context of this invention amino represents NH a »NH-alkyl or N (al qui 1 o) a» wherein alkyl is as defined above. In a more specific aspect, the novel derivatives of indolo-2,3-d ono-3-oxi a of the invention are? -met i 1 -5- (4- (IM. N-di meti 1 su1 fanoi 1) feni 1) -6-7-8-9-tetrahy dro-lH-pi rro1 oC3 »2-hL3-i soqui no1 i no-2.3-di ono-3-0- (3- (2-o? O) tetrahydrof ri 1) o? ima; 8-methyl-5- (4- (l \ IN-dimethylsulfamoyl) phenyl) -e-7-B-9-tetrahydro-lH-p rroloC3.2h3-isoquinol ino-2,3-diono-3-0- (5- (4-bromo-3-metho? I) so? Azole and methyl) oxime; B-methyl-5- (4- (l \, N-dimethylsulfamoyl) phenyl) -6-7-β-9-tetrahy dro-lH-pi rro1 oC3 »2h Di soqui no1 i no-2, 3-di ono-3-0- (5- (4-bromo-3-ethoxy) iso? azol i lmeti l) o? ima; B-methyl-5- (4- (N, N-dimethylsulfamoyl) phenyl> -s-7-B-9-tetrahy dro-lH-pi rro 1 oC3 »2h] -i soqui no1 i no-2» 3 -di ono-3-0- (4- (IM »5-dimeti 1-3-oxo) isoxazole i 1 ethyl) oxime» 8-met l-5- (4- (N, N-dimethylsulfame l) phenyl) -e-7-8-9-tetrahydro-lH-pyrroloC3.2h3-isoqui oli or-2.3-diono-3-0- (4- (IM- eti 1-5-tercbuti 1-3-o? o) iso ? azol i lmet 1) or? ima;
17
8-met l-5- (4- (N. N-dimet lsulfamoyl) phenyl) -6-7-8-9-tetrahydro-lH-pyrro1oC3.2hD-isoquin indo-2 »3-di ono-3-0 - (4- (5-met 1-3 -metho?) Isoxazole imeti 1) oxime »or 8-met l-5- (4- (NN-dimethyl sulfamoyl) fem" l) -6-7-8- 9-tetrahydro-lH-? Irro1oC3.2hL3-isoqui no1 ino-2 »3-diono-3-0- (4- (5-methy1-3-etho) iso? Azole i Imet 1) o ma» 0 a pharmaceutically acceptable salt thereof In another specific embodiment, the novel indolo-2'-3-dione-3-oxam derivatives of the invention are 1-methyl-8-met-1-5-phene-6. »8» 9 -tetrahydro-pyrrolo
C3 »ZhLJisoqu nol i no-2,3-d ono-3-0 (carbo? Imet 1) or? Ima» 1-methi 1-8-meti 1-5-phenyl-6 »7» 8 »9 -tetrahydro -lH-pyrrolo C3.2h.Hsoq inol ino- 2.3-diono -3-0- (eto? icarboni lmeti 1) o? ima; 1- methyl-B-methyl-5- (4- (NN-dimethylsulfamoi 1) pheny1) - 6.7.8.9- tetrahydro-pyrroloC3.2h3 isoquinol ino-2 »3 -dione -3-0- (carbo? Imeti 1 ) or? ima »1-methyl-8-methyl 1-5- (4- (N, N-dimethyl sulfamoyl) phenyl) -6» 7.8 »9- tetrahydro-lH-pyrroloC3» 2h3 isoquinol ino-2 »3 - diono -3-0- (l-eto icarboni 1-1-meti let 1) o? ima; LL-methyl-8-methyl-1-5- (- (N »N-dimethylsulfamoyl) phenyl) -6.7» 8 »9-tetrahydro-pyrroloC3» 2h3 isoquinol ino-2.3 -dione -3-0- (eto? Icarboni lmeti 1) o? Ima »8-methy1-5-pheny1-6» 7,8 »9-tetrahydro-lH-pi rro1 oC3» 2-h 1-ißoquinol ino-2,3-diono-3-0- (carbo ? imet 1) or ma; 8-met 1-5-phen-1-S, 7, 8 »9-tetrahydro-lH-pyrro1oC3» 2-h 1-
18
isoquinol i i no-2 »3-di ono-3-0- (1-carbo? i-1-met let l) o? ima» B-methyl-5-phenyl-6 »7.8,9-tetrahydro-lH- pyrroloC3,2-h3-isoquinol i na-2 »3-diono-3-0- (ethoxycarboni 1meti 1) or? ima» B-met l-5-pheny l-6.7 »B» 9-tetrahydro-lH-pyrroloC3 »2-hD-isoquinoli or-2» 3-dione-3-0- (isoporpocarboni Imeti 1) o? Ima; 8- et l-5-pheny l-6 »7» B »9-tetrahydro-lH-pyrroloC3.2-h] -isoqui nol i no-2.3-diono-3-0- (1-ethocarbaryl 1- 1-meti 1) eti 1 o? Ima; B- et l -5-phenyl -6.7.8.9-tetrahydro-lH -pyrrolo C3.2-h3-isoquinol ino- 2,3- diono-3 -0- (t, -buto? Icarboni Imeti 1) o? Ima; B-meti 1-5-phen l-6.7,8 »9-tetrahydro-lH-pyrroloC3.2-h3-isoquinol no-2» 3-di ono-3-0- (»N-dimeti 1 carbamoi 1meti 1) o? ima; 8-methy1-5-pheny1-6.7 »8» 9-tetrahydro-lH-pi rro1 oC3 »2- 1 -isoqui ol ino-2» 3-diono-3-0- (N-meti 1 carbamoi I eti 1) o? Ia; B-met 1-5-fe i 1-6.7, B »9-tetrahydro-lH-pyrroloC3» 2-h: -isoquinol i o-2,3-diono-3-0- (N-feni Icarbamoi Imeti 1) o? ima; B-meti 1-5-pheny1-6,7,8 »9-te rahydro-lH-pi rro1 oC3.2-h3-isoquinoline-2,3-dione-3-0 - (N» N - di (2 - hydroxyethyl) carbamoi 1methyl) oxime »B-methyl 1-5-phenyl-6» 7 »B» 9-tetrahydro-lH-pyrroloC3.2-h3-isoquinol no-2 »3-dione-3-0- (morfol inocarbon Imethyl) oxime; B-meti 1-5-fem '1-6, 7, B.9-tetrahydro-lH-pyrroloC3 »2-h3-isoquinoline-2» 3-dione-3-0 - (eto-icarboni lmeti lcarbamoil-meti 1 ) or? ima; B-meti 1-5-phenyl-6,7 »8» 9-tetrahydro-lH-pyrroloi: 3 »2-h3-isoquinoline-2,3-dione-3-0 ~ (N» -di (2-N »N- dieti lami no) ethyl)
19
carbamo 1) o? ima »B-meti l-5- (4- (NN-dimethylsulfamoyl) phenyl) -6,7,8,9-tetrahydro-1H-pyrroloC3.2-h3- isoquinol non-2,3-dione-3 - 0- (carbo? Imeti 1) or? ima; 8-methyl-5- (4- (NN-dimethylsulfamoi 1) pheny1) -6,7,8,9-tetrahydro-1H-pyrroloC3.2-h3-isoquinol ino- 2 »3-d ono-3- 0- (2-hydro? Iet l) o? Ia; 8-methyl-5- (4- (N, N-dimethylsulfamoyl) phenyl) -6,7,8,9-tetrahydro-1H-pyrroloC3 »2-h3-isoquinol ino-2,3-dione-3 -0- (l- carbo? i-1-methylethyl) or ima; 8-met l-5- (4- (N, N-dimethylsulfa oi 1) phenyl) -6,7,9,9-tetrahydro-1H-pyrroloC3.2-h3-isoquinol ino- 2 »3-dione-3- 0- (etho? -carbonylmethyl) or? Ima; 8-methyl-5- (4- (N, N-dimethylsulphamino 1) phenyl) -6,7,8 »9-tetrahydro-1H-pyrroloC3» 2-h3-isoquinol ino- 2 »3-dione-3 -0 - (ciclopropi lmeto? i carbonil eti 1) o? ima; 8-methyl-5- (4- (NN-dimethylsulfamoyl) phenyl) -6, 7.8,9-tetrahydro-1H-pyrroloC3 »2-h3-isoquinol ino- 2» 3-dione-3 -0- (isopropocarboni Imeti l) o? Ia; B-meti l-5- (4- (NN-dimethylsulfame l) phenyl) -6 »7.8.9-tetrahydro-1H-pyrroloC3» 2-h3-ißoquinol non-2,3-dione-3 -0- (NN-di) eti 1-carbamoyl methyl) or ia; 8-methyl-5- (4- (NN-dimethyl sulfamoyl) phenyl) -6, 7.8,9-tetrahydro-1H-pyrroloC3.2-h3- isoquinol ino-2,3-dione-3 -0- (piperi di nocarboni) lmet l) oxime; 8-methyl-5 - (4 - (piperidinosulfoni 1) phen 1) - 6,7,8,9-.
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tetrahydro-1H-pyrroloC3 »2-h3-isoquinol ino-2,3-dione-3 -0- (piperidinocarboni-1-methyl) oxime; B-met l-5- (4- (NN-dimethylsulfame 1) phenyl) -6,7,8 »9-tetrahydro-1H-pyrroloC3,2-h3-isoquinol ino-2,3-dione-3 -0- (orfolcarboni) lmeti 1) oxime; or 8-raeti l-5- (4- (N. -dimeti lsul famoyl) phen l) -6.7 »8,9-tetrahydro-1H-pyrroloC3.2-h3- isoquinol non-2,3-dione-3 - 0- (4-Hydro ibutyl-2-yl) oxy acid; or a pharmaceutically acceptable salt thereof.
Isomers This isos
Some of the chemical compounds of the present invention exist in (+) and) -) forms as well as in racemic forms. The racemic forms can be resolved at the optical antipodes by known methods, for example, by separating diastereomeric salts thereof, with an optically active acid, and releasing the optically active amine compound by means of treatment with a base. . Another method to resolve antipodes in the optical antipodes is based on chromatography on an optical active matrix. The racemic compounds of the present invention can be resolved into their optical antipodes, e.g., by fraction crystallization, for example, of d- or 1- (tartrate, andelate or ca-sulfonate) salts.
twenty-one
The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by means of the reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as the phenylalanine derivative (+> or (-). ) »Phenylglycine (+) or (-)» campanic acid (+) or (-) or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for the resolution of optical isomers are known, such methods include those described by Jaques J, Collet A »&Wilen S in" Enantiomers, Racemates and Resolutions ", John W law and Sons» New York (19B1). In addition, since they are chemical compounds of the invention, they can be divided into two syn- and antiform forms, depending on the arrangement of the substituents around the double bond of -C = N- A chemical compound of the present invention can thus be syn- or antiform »or it can be a mixture of these.
Seles Fa maggyH? Igfrfflenlfe Fair
The new derivatives of idol-2 »3-diono-3-o? of the invention can be provided in any suitable way
22
for the intended administration. Suitable forms include pharmaceutically (ie, physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic addition salts such as hydrochloride »hydrobromide» phosphate, nitrate »perchlorate» sulfate »citrate» lactate. tartrate »maleate» fumarate »mandelato. benzoate »ascorbate cinnamate. benzenesulfonate. methanesulfonate. stearate succinate. glutamate. glycolate. toluene-p-sulfonate. format »malonate» naphthale-2-sulfonate. salicylate and acetate. Such salts are formed by methods well known in the art. Other acids such as oxalic acid, while not pharmaceutically acceptable in themselves, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound and its pharmaceutically acceptable acid addition salt. The metal salts of a chemical compound of the invention include alkali metal salts, such as the sodium salt, of a chemical compound of the invention which contains a carbo-group. the chemical compound of the invention can be provided in a resolved or loose form together with pharmaceutically acceptable solvents such as water. ethanol and the like. In general, for the purposes of this invention the
2. 3
Resolved forms are considered equivalent to dissolved forms.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. Although another compound of the invention can be administered for use in therapy in the form of the starting chemical compound, it is preferred to introduce the active ingredient "optionally in the physiologically acceptable salt form in the pharmaceutical composition together with one or more excipients" vehicles and / or diluents. In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and optionally. other therapeutic and / or prophylactic ingredients. The vehicle (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Pharmaceutical compositions suitable for oral administration, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including intramuscular.
24
subcutaneous and intravenous), or in a manner suitable for administration by inhalation or insufflation. The chemical compound of the invention "together with a conventional vehicle, carrier or diluent can be placed in the form of pharmaceutical compositions and unit doses thereof" and thus be employed as solids, such as filled tablets or capsules, or liquids such as solutions, suspensions, emulsions »elí? or capsules filled therewith »all for oral use» in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parental use (including subcutaneous). Such dosage compositions and dosage unit forms may comprise conventional ingredients in conventional proportions with or without additional active compounds or principles, and said dosage unit forms may contain any suitable effective amount of the active ingredient in proportion to the daily dose scale. intended to be used. Therefore, compositions containing ten (10) milligrams of the active ingredient or. more broadly, from 0.1 to one hundred (100) milligrams per tablet, are suitable representative dosage forms. The chemical compound of the present invention can be administered in a wide variety of oral and parental dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention
or a pharmaceutically acceptable salt of a chemical compound of the invention. To prepare the pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, dragees, suppositories and dispersible granules. A solid vehicle can be one or more substances that can also act as diluents. flavoring agents »solubilizers» lubricants, suspending agents »binders» preservatives »tablet disintegrating agents or an encapsulating material. In the powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets »the active component is mixed with the vehicle having the necessary binding capacity in suitable proportions and compressed in the desired shape and size. The powders and tablets preferably contain five or ten to approve. about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, starch, gelatin, tragacanth, methylcellulose. carbo? i eti Icelulosa de sodio, a low melting wax, cocoa butter and the like. The term "preparation"
26
it is intended to include the formulation of the active compound with encapsulating material as a vehicle providing a capsule in which the active component, with or without vehicles, is surrounded by a vehicle, which in turn is associated therewith. Similarly, pills and pills are included. Tablets, powders, capsules, pills, dragees and tablets can be used as solid forms suitable for oral administration. To prepare suppositories »a low melting wax» such as a mixture of fatty acid glycerides or cocoa butter »first melt and the active component is dispersed homogeneously therein» by stirring. The molten homogeneous mixture is then poured into molds of suitable size, it is allowed to cool and thus solidifies. Compositions suitable for vaginal administration may be presented as "tampon" ointments creams, gels »pastes» foams or sprinklers containing in addition to the active ingredient the carriers known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propyl 1 solutions. For example, liquid preparations for parental injection can be formulated as solutions in aqueous polyethylene glycol solution. The chemical compound according to the present invention can thus be formulated for administration
27
parental (eg, by injection »eg» bolus injection or continuous infusion) and can be presented as a unit dose in ampoules »pre-filled syringes. infusion of small volume or in multiple dose containers with an added condom. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as stabilizing and / or dispersing suspending agents. Alternatively, the active ingredient may be in the form of a powder obtained from aseptic isolation of sterile solid or by means of a solution of constitution for constitution with a suitable vehicle, eg, "pyrogen-free water", before to be used. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable stabilizing and flavoring colorants and thickeners. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material "such as natural or synthetic gums" resins, methylcellulose, sodium carbohydrate, cellulose, and other well-known suspending agents. Preparations are also included in a single form. which are intended to be converted, a little before use, into liquid form preparations for oral administration. Such liquid forms include solutions »suspensions and
2B
emulsions. These preparations may contain »in addition to the active component» coloring agents. flavors. Stabilizers, pH regulators. artificial or natural sweeteners »dispersants» thickeners »solubilizers and the like. In accordance with the invention for topical administration to the epidermis the chemical compound can be formulated as ointments »creams or lotions or as transdermal patches. For example, ointments and creams can be formulated with an aqueous or oily base with the addition of suitable thickeners and / or gel activators. The lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, commonly sucrose or acacia or tragacanth; the tablets comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid vehicle. The solutions or suspensions are applied directly to the nasal cavity by conventional means »for example with a dropper» pipette or sprinkler. The compositions can be
where R3 represents a substituted or unsubstituted trivalent hydrocarbon radical containing from 4 to 40 carbon atoms or more, such as, for example, trivalent acyclic radicals or trivalent cyclic radicals, such as, for example, trivalent alkylene radicals, such as, for example, hydrocarbon derivatives; , 2,2-trimethylolpropane and the like, or trivalent cycloalkylene radicals such as, for example, the 1,3-trihydro-cyclohexane derivative, and the like. Such hand organophosphates can be described in greater detail, for example, in U.S. Patent No. 4,567,306, the disclosure of which is incorporated herein by reference. The diorganophosphites representing ivos can include those with the formula:
(neither)
where R 4 represents a radical of substituted or unsubstituted dihydric hydrocarbon containing from 4 to 40 carbon atoms or more and W represents a radionuclide of substituted monovalent or unsubstituted hydrocarbon which contains 1 to 18 carbon atoms or more. Substituted monohydric radicals substituted and not
Representative substitutes represented by W in the above formula (III) include alkyl and aryl radicals, while substituted and unsubstituted divalent hydrocarbon radicals represented by R 4 include divalent acyclic radicals and divalent aromatic radicals. Exemplary divalent acyclic radicals include, for example, alkylene, alkyne-o: < i) Xkylene, alkyl-NX-akylene wherein X is hydrogen or a substituted or unsubstituted monovalent hydrocarbon radical, alkylene-S-alkylene, and cycloalkylene radicals, and the like. The most preferred divalent acyclic radicals are the divalent alkylene radicals such as those presented in greater detail in US Patent Nos. 3,415,906 and 4,567,302 and the like, the disclosure of which is incorporated herein by reference. Exemplary divalent aromatic radicals include, for example, arylene, bisarylene, aryne-aikin, aryne-alkylene-ary, arylene-o-arylene, aryne-NX-arylene, where X is in accordance with the above defined, ari leno-S-ari log, and arylene-S-alkylene, and the like. More preferably, R4 is a divalent aromatic radical such as those presented in more detail in US Patents Nos. 4,599,206 and 4,717,775, and the like, the presentation of ions of which are incorporated herein by reference.
Representatives of a most preferred class of diorganophosphites are those of the formula:
(IV)
where W eß according to Jo defined above, each Ar eß equal or different and represents a substituted or unsubstituted aryl radical, each y is the same or different and is a value of 0 or 1, represents a divalent bridge group selected from -C (R5) 2-, -0-, -S-, -NR6-, Si (R7) 2- and -CO-, where each R5 is the same or different and represents hydrogen, alkyl radicals having from 1 to 12 carbon atoms, phenyl, tolyl, and anisyl, R6 represents hydrogen or a methyl radical, each R7 is the same or different and represents hydrogen or a methyl radical, and m has a value of 0 or 1. Such diorganofoßf i tos describe in greater detail, as for example in US Patents Nos. 4,599,206, 4,717,775 and 4,835,299, whose ions are incorporated herein by reference. Triorganophosphites represented may include those with the formula:
wherein each R8 is the same or different and e is a substituted or unsubstituted monovalent hydrocarbon radical, for example, an alkyl, cycloalkyl, aryl, alkaryl and aralkyl radical which may contain from 1 to 24 carbon atoms. Suitable hydrocarbon radicals may contain from 1 to 24 carbon atoms or more and may include the deßcri or β above in Rl in the formula (I). > Exemplary triorganofoßfitoß include, for example, trialkylphosphites, dialkyl larylphosphite, alkylsulfites, triarylphosphites, and the like, such as, trimethyphosphite, triethyl phosphite, butyldiethylphosphine, tri-n-propylphosphite, tri -n-dodecylphosphite, tri-2-yl lhexylphosphite, tri-n-octylphosphite, tri-n-butylphosphite, tri-2-ethylhexy Ifosphite, tri-n-oc ilphosphite, tri-n-dodecyl phosphite, dimethylphosphite, diethylphenium phosphite, ethyldiphenyl phosphite, ethyldiphenylphosphite, triphenyl phosphite, trinafylphosphite, bis (3,6,8-tri-t-bu and 1-2-naphthiD and ilphosphite, bis ( 3,6,8-tri-t-bu i 1-2-naphthyl (cyclohexylphosphite, tris (3,6-di-t-butyl-1-2-naphthyl) phosphite or, bis (3,6,8-tri) -t-but i-2-naph i 1) (4-bipheniDfasf ito, bis (3,6,8-tri-t-butyl-2-
naphthyl) phenylisphi, is (3,6,8-tri-t-but i i, 1-naphthi 1) (4-benzoylphenophosphite, bi (3,6,8-tri-t-but i 1-2 -nafti 1) (4-sulfonylphenyl) phosphite, and the like The most preferred triorganophosphite is triphenylphosphite, such triorganophosphites are described in greater detail, for example, in US Patents Nos. 3,527,809 and 5,277,532, the filings of which are incorporated herein by reference. they are hereby incorporated by reference: organopol ifoes and representati voß contain two or more tertiary phosphorus atoms (trivalent) and may include the formula:
where XI represents a substituted or unsubstituted n-substituted hydrocarbon bridge radical containing from 2 to 40 carbon atom, each R9 is the same or different and is a divalent hydrocarbon radical containing from 4 to 40 carbon atom, each RIO is the same or different and is a substituted or unsubstituted monovalent hydrocarbon radical containing from 1 to 24 carbon atoms, a and b may be the same or different and each has a value from 0 to 6, provided that the sum of a + b is 2 to 6 and n is equal to a + b. Obviously, it will be understood that when a has a value
of 2 or more, each radical P.9 may be the same or different, and when b has a value of 1 or more, each RIO radical may also be the same or different. Steady-state idrocarbon bridge radicals represented by XI, as well as representative divalent hydrocarbon radicals represented by R9 above, include aromatic radicals and acyclic radicals with, for example, alkylene, alkali-Qm-alkylated radicals. ene, cycloalkylane, arylene, bisarylene, arylene-alkylalene, and aryl- (CH2) y- m- (CH2) y -arylene, and the like, where Q mey are in accordance with that defined above for the formula (IV ). The most preferred acyclic radicals represented by XI and R9 above are divalent alkyl radicals, while the more preferred aromatic radicals represented by XI and R9 above are divalent arylene and bisarylene radicals such as for example those described in greater detail in the US Pat. North American Nos. 4,769,498; 4,774,361; 4,885,401; 5,179,055; 5,113,022; 5,202,297; 5,235,113; 5,264,616 and 5,364,950, and in European Patent Application Publication No. 662,468, and the like, the presentations of which are incorporated herein by reference. Representative monovalent hydrocarbon radicals represented by each RIO radical above include alkyl and aromatic radicals. Illustrative preferred organopolies may include
bißfosfitoß as for example those of the formulas (VID a (IX) below:
wherein each R9, RIO and XI of the formulas (VID to (IX) ßon are the same as those described above for the formula (VI). Preferably, each R9 and XI represents a divalent hydrocarbon radical selected from alkylene, arylene, -alkylene-arylene, and bisarylene, while each RIO represents a monovalent hydrocarbon radical selected from alkyl and aryl radicals Organophosphite ligands of such formulas (VI) to (IX)
they can be found, for example, in the North American Patent Noß. 4,668,651; 4,748,261; 4,769,498; 4,774,361; 4,885,401; 5,113,022; 5,179,055; 5,202,297; 5,235,113; 5,254,741; 5,264,616; 5,312,996; .5,364,950; and 5 391,801; whose pre sentation is included here by reference. Representative of most preferred claßß of organobiefosf i tos ßan loe of the following formulas (X) to (XII):
oai) where A,, R9, RIO, XI, m and y are in accordance with the above defined. More preferably XI represents a divalent radical aryl- (CH2) y- (Q) m- < CH2) y-ari where each and indi id lly has a value of either 1; m has a value of O or 1 and is -O-, -S- or -C (R5) 2- where each R5 is the same or different and represents a hydrogen or methyl radical. More preferably, each alkyl radical of the above-defined RIO groups may contain from 1 to 24 carbon atoms and each aryl radical of the Ar, XI, R9 and RIO groups defined above of the formulas (VI) to (XII) may contain from 6 to 18 carbon atoms and said radicals can be the same or different, while the preferred alkylene radicals of XI can contain from 2 to 18 carbon atoms and the preferred alkylene radicals of R9 can contain from 5 to 18 beta atom. carbon. Further, preferably, the divalent Ar radicals and the divalent aryl radicals of XI of the above formulas are phenylene radicals wherein the bridging group represented by - (CH2) and- (Q) m- (CH2) y- is attached to
said phenylene radicals in ortho positions in relation to the oxygen atoms of the formulas connecting the phenylene radicals to their phosphorus atom of the formula. It is also preferred that any radical substituent when present in such phenylene radicals be attached in the para and / or ortho position of the phenylene radicals in relation to the oxygen atom which places the given substituted phenylene radical with its phenylene atom. match. Obviously, any of the radicals R3, R4, R8, R9, RIO, XI, XI, W, Q and Ar of such organophosphines of formulas (II) to (XII) above may be substituted if desired with any substituent suitable containing from 1 to 30 carbon atoms which does not adversely affect the desired result of the hydroformylation reaction. Substituents which may be in said radicals furthermore and correspondingly corresponding hydrocarbon radicals such as, for example, alkyl, aryl, aralkyl, alkaryl and cyclohexyl substituents may include, for example, silyl radicals such as for example -Si (P.12) 3; amino radicals such as for example -N (R12) 2; phosphine radicals such as -ari lo-P (R12) 2; acyl radicals such as for example -C (0) R12; acyloxy radicals such as for example 0C (0) R12; amido radicals such as -C0N (R12) 2 and -N (R12) C0R12; sulfonyl radicals such as -S02R12; alcaxjL radicals such as -0R.12; sulfinyl radicals as per
example -S0R12; sulfenyl radicals such as -SR12; phosphonyl radicals such as for example -P (0) (R12) 2; thus with halogen radicals, nitro, cyano, trifluoride, hydroxy, and the like, wherein each radical R2 is the same or different and represents a monovalent hydrocarbon radical having 18 carbon atoms (eg, alkyl radicals, aryl, aralkyl, alkaryl and cyclohexyl), provided that in amino substituents such as -N (R12) 2 each R12 as a whole can also represent a divalent bridge group forming a heterocyclic radical with the nitrogen atom and in substituents amido as for example -C (0) N (R.12) 2 and -N (R12) C0R12 where each R12 linked to N can also be hydrogen. And it will be understood, of course, that any of the groups of substituted or unsubstituted hydrocarbon radicals constituting a particular organophosphate may be the same as different. More specifically illustrative examples thereof include primary, secondary and tertiary alkyl radicals such as, for example, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, nea-pentyl, n-hexyl, amyl, sec-a ilo, t-amyl, iso-octyl, decyl, octadecyl, and the like; aryl radicals such as phenyl, naphthyl and the like; aralkyl radicals such as, for example, benzyl, phenylethyl, triphenyl, and the like; alkaryl radicals
such as tolyl, xylyl, and the like; alicyclic radicals such as, for example, cyclopentyl, cyclohexyl, 1-methylcyclohexyla, cyclooctyl, cyclohexyl, and the like; alco? i radicals such as methoxy, ethoxy, propoxy, t-butoxy, 0CH2CH2OCH3, - (0CH2CH2) 20CH3, - (0CH2CH2) 30CH3, and the like; aryloxy radicals such as phenoxy and the like; as well as silicone radicals such as for example -Si (CH3) 3; -Yes (0CH3) 3, -Yi (C3H7) 3, and the like; amino radicals such as for example -NH2, -N (CH3) 2, -NHCH3, -NH (C2 (H5), and the like; arylphosphino or for example -P (C6H5) 2 radicals, and the like, acyl radicals co or example -C (D) CR3, -C (0) C2H5, -C (0) C6H5, and the like, carbanyloxy radicals or for example -C (O) 0CH3 and the like, oxycarbanyl radicals such as -0 (C0) C6H5, and the like, amido radicals such as -C0NH2,
C0N (CH3) 2, -NHC (0) CH3 and the like; sulfonyl radicals such as for example -S (0) 2C2H5 and the like; sulfinyl radicals such as for example -S (0) CH 3 and the like; sulfenyl radicals or for example -SCH3, -SC2H5, -SC6H5, and the like; phosphonyl radicals such as for example -P (0) (C6H5) 2, -P (0) (CH3> 2,
P (0) (C2H5) 2, -PÍO) (C3H7) 2, -P (0) (C4H9) 2, -P (O) (C6H13) 2, -P (0) CH3 (C6H5), -P ( 0) (H) (C6H5), and the like. Specific illustrative examples of organophosphate ligands include the following: 2-t-butyl 1-4-methoxy-phenyl (3,3'-di-t-b-5,5'-dimethoxy-1,1 '-
biphenyl-2,2'-diyl) phophite which has the formulas
Ligand A methyl < 3,3'-di-t-butyl-5,5 * -dimetho-i-1'-biphenyl-2,2'-dihydrophosphite having the formula:
Ligand B 6,6'- ((4,4'-boei, 1-dimethylethyl) - (1,1'-hydrophyl) -2,2'-diyl) bie (oxy)) bis-dibenza (d, f) (1,, 2) -diox phosphope that has the formula:
Ligand C6.6 '- (< 3,3 * -biß (l, 1-dimelethyl) -5,5'-dimetho? I- (l, l * -bifen? L) -2.2'- diyl biß (o? i)) bis-dibenzo (d, f) < l, 3,2) gave? afosfepine which has the formula:
Ligand D 6, '- ((3,3'-5,5'-tetrahist (1,1-dimepropy 1) - (1, 1 * -biphenyl) 2,2 * -diyl) bis (o? I) ) bis-dibenzo (d, f) (1, 3,2) diaxaphosphine having the formula;
Ligand E 6? 6 * - ((3,3'-5,5'-tetraquiß (1, l-dimethylethyl) -l, l '-bif eni-2,2'-diyl > bis (oxy)) bis -dibenzo (d, f) (1, 3,2) -dia? afasf epine that has the formula:
Ligand F (2R, 4R) -di (2,2 '- (3,3'-5,5 * -te raquis-tert-amii-l, l biphenyl)) -2,4-pentyldiphosphite having the formulas
Ligand G (2R, 4R) -di (2,2 '- (3,3'-5,5'-tetrakis-tert-butyl-1, f-biphenyl) -2,4-pentyldiphophite having the formula :
CHa *. -CH CH3
Ligand H (2R, 4R> -di (2,2 '- (3,3'-di-amyl-5,5'-dimethoxy-1, 1'-bifinyl)), 4-pentyldiphosphite having the formula:
Ligand I
(2R, 4R) -di (2,2 '- (3,3'-di-tert-butyl-5,5'-dime-il-1, 1-biphenyl) -2,4-pentyldiphosphite having the formula:
Ligand J (2R, 4R) -di (2,2 '- (3,3'-di-tert-buyl-5,5'-diettoyl, 1-biphenyl) -2,4-pentyldiphosphite which has the formula:
Ligand (2R, 4R) -di (2,2 * - (3,3'-di-tert-butyl-5,5'-die il-1, 1 * -biphenyl) -2,4-pentyldiphosphite which has the formula:
Ligand L (2R, 4R) -di (2,2 '- (3,3'-di-tert-butyl-5,5'-dip.etoxy-1, 1'-biphenyl) -2,4-pentildiphosph It has the formula:
Ligand M 6 - ((2 '- ((4,6-bis (1,1-dimethylethyl) -l, 3,2-benzodio? A phosphol-2-yl) or? I) -3,3'- bis (1, 1-dimethylethyl) -5,5'-dimetho? i (1,1 * -biphenyl-2-yl) oxy) -4,8-b iß (1, 1-dimethylethyl) -2, 10 -dimetoxidibenzo (d, f) (1, 3,2) dioxafasf epine having the formula:
Ligand N 6- (< 2 '- ((l, 3,2-benzodio? Afoßfol-2-il or? I -3,3'-biß (l, l-
dime i le il) -5,5-dimethoxy (1,1'-biphenyl) -2-yl or i) -4,8-bis (l, 1-dimethylethyl) -2, 10-dimetho-idibenzo (d) , f) (1, 3,2) gave? afosphepin which has the formula:
Ligand 0 6 - ((2'- < (5,5-dimethyl-l, 3,2-dio? Afosforin-2-yl) oi) -3,3'-bis (l, l-dimethylethyl) -5 , 5'-dimetho? I (1,1'-biphenyl) -2-yl) oi) -4,8-biß (1, 1-dimeti leti 1) -2, 10-di etho? Idibenzoid, f) ( 1, 3,2) dio? Afoßfepina that has the formula:
Ligand P biß (4-he? Ilphenyl) ester of 2 '- ((4,8-bis (l, 1-dimethylethyl) -2, iO-dimetho-idibenzo (d, f) (1, 3.2) - dio? afoßfepin- -il) or? i) - 3,3'-biß (1, l-dimethylethyl) -5,5 * -dimetho? i (1, 1-biphenyl) -2-yl of foephorous acid which has the formula:
Ligand Q phosphorus ester of 2- ((2- ((4,8-biß (1, 1-dimeti leti 1), 2,10-dimeta? Idibenzo- (d, f) (1, 3,2) dioxofoßfepin -6-yl) or? I) -3- (1,1-dimethyl-ethyl) -5-methoxyphenyl) methyl) -4-methoxy, 6- (l, 1-di-ethylethyl) phenyl-diphenyl Phosphorous acid that has the formula:
Ligand R 3-metho-l, 3-cyclohexamethylene te raquis (3, - is (1,1-dimethylethyl) -2-naphthialenyl) ester of phosphorous acid having the formula:
Ligand S 2,5-biß (1, 1-dimethylethyl) -l, 4-phenylene te raquiß (214-iß (, 1-dimethyl-lethyl) phenyl) ester of phosphorous acid having the formula:
Ligand T ester of methyl lendi-2, 1-phenylene tetrakis (2,4-bisd, 1-dimelethyl) pheni l) ester of phosphorous acid having the formula:
Ligand U (1,1 * -biphenyl) -2,2'-diyl tetrakis (2-U, 1-dimethylethyl) -4-metho? Ifenyl) ester of phosphorous acid having the formula:
Ligand V As previously observed, the metal-organophosphorus ligand complex catalysts that can be employed in this invention can be formed by methods known in the art. Metal-organophosphorus ligand catalysts are preferably present in homogeneous form. For example, rhodium preformed catalysts hydrido-carbonyl-organophosphorus ligand can be prepared and introduced into the reaction mixture of a particular process. More preferably, the metal-organophosphorus ligand catalysts can be derived from a rhodium catalyst precursor that can be introduced into the reaction medium for in situ formation of the active catalyst. For example, precursors of catalysts of rhodium talee as dicarboni lacetonato rhodium lacetonate, Rh203, Rh4 (C0) 12, Rh6 (C0) 16, Rh (N03) 3 and eimilaree can be introduced into the reaction mixture together
with the organophosphorus ligand for the in situ formation of the active catalyst. In a preferred embodiment of this invention, rhodium dicarbony lacetonate lacetonate is used as a rhodium precursor which reacts in the presence of a solvent with the organophosphorus ligand to form a precursor of the rhodium-1 igand organophosphorus catalytic complex that is introduced into the reaction zone together with excess (free) organophosphorus ligand for in situ formation of the active catalyst. Either way, it is sufficient for the purpose of this invention that the monomer of carbon, hydrogen and organophosphorus compounds are all ligands capable of forming complexes with the metal and that an active metal-organophosphorus ligand catalyst is present in the mixture of the reaction under the conditions used in the hydroforming reaction. More partarly, a catalyst precursor composition can be formed which essentially consists of a metallo-phosphorus organophosphorus ligand precursor catalyst, an organic solvent and free arganoforphor ligand. Such precursor compositions can be prepared by forming a solution of an initial rhodium material such as, for example, rhodium oxide, hydride, carbonyl or salt, for example, a nitrate, which may or may not be in complex combination with a
organophosphorus ligand in accordance with what is defined herein. Any suitable rhodium starting material can be used, for example, rhodium dicarbonilaceti lacetonate, Rh2Q3, Rh (C0) 12, Rh6 (C0) 16, Rh (N03) 3, and rhodium carbonyl hydrides arganophosphorus ligand. Carbonyl and organophosphorus ligands, if they are not yet forming complexes with the initial rhodium, can form complexes with the rhodium either before the process or during in situ processing. By way of illustration, the preferred catalyst precursor composition of this invention consists essentially of a rhodium carbonyl complex precursor catalyst solubilized organophosphorus ligand, a solvent and optionally free organophosphorus ligand separated by the formation of a dicarbonyl acetylacetonate solution of rhodium, an organic solvent and an organophosphorus ligand according to the definition herein. The organophosphorus ligand readily replaces one of the carbonyl ligands of the rhodium acetyl acetonate complex precursor at room temperature as can be seen by the evolution of the carbon monosurved gaß. This substitution reaction can be facilitated by heating the solution, if desired. Any suitable organic solvent can be used in which the precursor of the rhodium dicarbonate laceti lacetonate complex and the
Rhodium complex precursor and organophosphorus ligand are soluble. The amounts of the rhodium complex catalyst precursor, organic solvent and organophosphorus ligand, as well as their preferred embodiments present in such catalyst precursor compositions can obviously correspond to the amounts that can be employed in the processes of this invention. Experience has shown that the acetylacetonate ligand of the precursor catalyst is replaced after the process, eg, hydroformylation, has started with a different ligand, such as hydrogen, carbon monoxide or organophosphorus ligand, to form the catalyst of an active complex in accordance with what has been explained above. The acetyl acetone released from the precursor catalyst under hydroformylation conditions is removed from the reaction medium with the product aldehyde and therefore does not adversely affect the hydroformylation process. The use of such preferred compositions of rhodium complex catalytic precursor offers a simple economical simple method for handling the rhodium precursor and the initiation of hydroformylation. Accordingly, the organophosphorus metal-ligand complex catalysts employed in the processes of this invention consist essentially of metal forming complexes with carbon monoxide, i.e.
hydroformylation, and an organophosphorus ligand, said ligand is bound (forming complexes) with the metal in a chelated and / or non-chelated form. In addition, the terminology "consists essentially of", as used here, does not exclude but includes the hydrogen that forms complex with the metal, in addition to mono? gone of carbon and the arganophosphorus ligand. Furthermore, said terminology does not exclude the possibility of other organic ligands and / or anions which can also form complexes with a metal. Materials in quantities that nega- tively poison or deactivate the catalyst are undesirable and therefore the catalyst is more desirably free of contaminants such as halogen bound to metals (eg, chlorine and the like) as long as it can not be absolutely necessary. Hydrogen and / or carbonyl ligands of a metal-organophosphorus ligand catalyst may be present as a result of being ligands attached to a precursor and / or co-catalyst or result of in-situ formation such as for example due to hydrogen gases and carbon monomer employed in the hydroforming process of the ion of this invention. As previously observed, organophosphorus ligands can be used both as a metal-organophosphorus ligand catalyst ligand as well as an organophosphorus ligand.
free organophosphorus which may be present in the reaction medium of the processes of this invention. Further, it will be understood that while the organophosphorus ligand of the metal-organophosphorus ligand-catalyst catalyst and any excess free orgapaf-phosphorus ligand that are preferably present in a given process of this invention are usually the same type of ligand, different types of organophosphorus, as well as mixtures of two or more ligands different from organophosphorus and can be used for a defined purpose in each given process ßi ße wishes. The amount of organophosphorus metal-ligand catalyst present in the reaction medium of a given process of this invention should be only the minimum amount necessary to provide the given metal concentration desired for its use and which provides the basis for at least the catalytic amount of metal needed to catalyze the particular process desired. In general, metal concentrations in the range of about 1 part per million to about 10,000 parts per million, calculated as free metal, and molar proportions between ligand and metal in the catalyst solution ranging from about 1: 1 or less to about 200 : 1 or more, should be sufficient for most processes. As previously observed, in addition to the catalysts of
metal-ligand complex of organophosphorus, the processes of this invention and especially the hydroformylation process can be carried out in the presence of free organophosphorus ligand. While the processes of this invention can be carried out in any excess amount of desired free organophosphorus ligand, the use of free organophosphorus ligand may not be absolutely necessary. Accordingly, in general, ligand amounts of about 1.1 or less to about 200, or more if desired, moles per mole of metal (e.g., rhodium) present in the reaction medium should be suitable for most of the purposes, especially in relation to rhodium-catalyzed hydroformylation; said amounts of ligand employed are the sum of the amount of bound ligand (which forms complex) with the metal present and the amount of free ligand (which forms complexes) present. Obviously, if desired, compensating ligand can be supplied to the reaction medium of the process, at any time and in any suitable manner in order to maintain a predetermined level of free ligand in the reaction medium. The permissible conditions of the reaction that can be employed in the processes of this invention are chosen, and ideally, according to the particular syntheses desired. Taleß process conditions are well known in the art. All processes
of this invention can be carried out in accordance with conventional procedures known in the art. Illustrative conditions of the reaction for carrying out the processes of this invention are described, for example, in irk-Oth er, Encyclopedia of Chemical Technology, Fourth Edition, 1996, the relevant parts of which are incorporated herein by reference. According to the particular process, the operating temperatures may be within a range of about -80 ° C or less to about 500 ° C or more, and the operating pressures may be within a range of about 1 pound per square inch read in the gauge or less to approximately 10,000 pounds per square inch read on the gauge or more. The processes of this invention are carried out for a period of time sufficient to produce the desired products. The exact time of the reaction that is employed depends, in part, on factors such as temperature, pressure, nature and proportion of the initial materials, and the like. The reaction time will normally be within the range of about one half hour to about 200 hours or more, and preferably less than about one hour to about 10 hours. The processes of this invention and preferably the process
of hydroformylation can be carried out in the presence of an organic solvent for the metal-organophosphorus ligand catalyst. The solvent may also contain dissolved water up to the saturation limit. According to the particular catalyst and the reagents employed, suitable organic solvents include, for example, alcohols, alkanes, alkenes, alkynes, ethers, aldehydes, ketones, esters, amides, amines, aromatics and the like. Any suitable solvent that does not interfere negatively with the intended processes may be employed and such solvents may include those commonly used to date in known metal-catalyzed processes. The fact of increasing the dielectric constant or the polarity of a solvent can generally tend to favor incremented reaction regimes. And indeed, mixtures of one or more different solvents can be used, if desired. It is evident that the amount of solvent employed is not a critical factor for the present invention and only a sufficient amount is required to provide the reaction medium with the particular metal concentration desired for a given process. In general, the amount of solvent when employed can be within a range of approximately 5 *? by weight up to about 99 * by weight or more based on the total weight of the starting materials of the reaction mixture.
The processes of this invention are useful for preparing optically active and non-optically active substituted and unsubstituted compounds. Illustrative compounds prepared by the processes of this invention include, for example, substituted and unsubstituted alcohols or phenols; amines; amides; ethers or epoxides; esters; cetanas aldehydes; and nitriles. Examples of suitable optically active and optically active compounds which can be prepared by the processes of this invention (including starting materials according to the above described) include the permissible compounds described in ir -Othme, Encyclopedia of Chemical Technology, (Encyclopedia de Chemical Technology), Fourth Edition, 1996, the relevant parts of which are incorporated herein by reference, and the Merck Index, An Encyclopedia of Chemical, Drugs and Biologicals, (The Merck Index, An Encyclopedia of Chemical Substances, Drugs and Biological Substances), Eleventh Edition, 1989, whose relevant parts are incorporated herein by reference. The desired products of this invention may be recovered in any conventional manner and one or more separators or separation zones may be employed in any given process to recover the desired product of the reaction from its crude product fluid of the reaction. Appropriate methods of separation include, for
example, solvent extraction, ion crystallization, distillation, vaporization, evaporation on rubbed film, descending film evaporation and ßimilareß. It may be desirable to remove the products from the crude reaction mixture as they are formed by the entrapment agent in accordance with that described in the published Patent Application of Patent Cooperation Treaty WO 88/08835. A preferred method for separating the product mixtures from the other components of the crude mixtures of the reaction is by membrane separation. Such membrane separation can be achieved in accordance with what is set forth in US Pat. No. 5,430,194 and in accordance with the co-pending US Patent Application Serial No. 08 / 430,790, filed May 5, 1995, mentioned above. The processes of this invention can be carried out in the form of lots or continuously, with recycling of the initial materials not consumed, if required. The reaction can be carried out in a plurality of reaction zones, in series or in parallel or it can be carried out in batches or continuously in an elongated tubular zone or in series of such zones. For example, a re-blended reactor can be used in series with the multi-stage reactor by first placing the backmixing reactor. The construction materials used
they must be inert to the initial materials during the reaction and the manufacture of the equipment must be able to resist the reaction temperature and the pressures. The means for introducing and / or adjusting the amount of initial materials or ingredients introduced in batches or continuously in the reaction zone during the course of the reaction can be conveniently employed in the processes, especially to maintain the desired molar ratio. of the initial materials. The steps of the reaction can be carried out by the incremental addition of one of the initial materials to the other. Likewise, the steps of the reaction can be combined by means of the joint addition of the initial materials. When a complete conversion is not desired or when a complete reaction can not be obtained, the initial materials can be separated from the product, for example, by distillation, and the starting materials are recycled back into the reaction zone. The processes can be carried out either in reaction equipment with glass lining, stainless steel or a similar type. The reaction zone can be equipped with one or more internal and / or external heat exchanger (s) to control undue temperature fluctuations or to avoid possible "out of control" temperatures of the reaction.
The processes of this invention can be carried out in one or more reaction steps and in more than one reaction step. The exact number of reaction steps and reaction steps will be dictated by the best camris between the capital costs and the achievement of a high selectivity of catalyst, activity, useful life and ease of operation capacity, as well as the intrinsic reactivity of the initial materials in question and the stability of the initial materials and the desired product of the reaction for the reaction conditions. Hydroformylation Processes A preferred process useful in this invention is hydroformylation. Hydroformylation processes catalyzed by illustrative organophosphorus metal-ligand complexes that may undergo such hydrolytic degradation of the organophosphorus ligand and catalytic deactivation include the processes described, for example, in U.S. Patent Nos. 4,148,830; 4,593,127; 4,769,498; 4,717,775; 4,774,361; 4,885,401; 5,264,616; 5,288,918; 5,360,938; 5,364,950; and 5,491,266; whose presentations are incorporated here by reference. Accordingly, the hydroformylation processing techniques of this invention may correspond to any known processing technique. The preferred processes are those that involve liquid recycling hydroforming processes
of cataizador. In general, such hydroformylation processes of liquid catalyst recycling include the production of aidehidoß by the reaction of an unsaturated olefinic compound with monomer of carbon and hydrogen in the presence of a metal-organophosphorus ligand catalyst in a liquid medium. which also contains an organic solvent for the catalyst and ligand. Preferably, the free organophosphorus ligand is also present in the liquid hydroformylation reaction medium. The recycling process generally includes the removal of a part of the liquid reaction medium containing the catalyst and the aldehyde product from the hydroformylation reactor (i.e., reaction zone), either continuously or intermittently, and the recovery of the aldehyde product therefrom by the use of a composite membrane or for example that presented in US Pat. No. 5,430,194 and copending US Patent Application Serial No. 08 / 430,790, filed May 5, 1995 , the disclosures of which are incorporated herein by reference, or by the more conventional preferred distillation method (i.e., vaporization separation) in one or more steps under normal, reduced or elevated pressure, as appropriate, in a separate distillation zone , the metal catalyst does not
Volatilized containing recycled waste to the reaction zone as presented, for example in US Patent No. 5,288,918. The condensation of the volatilized materials and the subsequent separation and recovery thereof, for example, by further distillation, can be carried out in any conventional manner, the crude aldehyde product can be transferred for further purification and separation of isomers, if It is desired, and the recovered reagents, for example, olefinic starting material and sinteßiß gas can be recycled in any desired manner to the hydroformylation zone (reactor). The recovered metal catalyst containing refined such membrane separation or recovered non-volatilized metal catalyst containing residue from said vaporization separation can be recycled to the hydroformylation zone (reactor) in any desired conventional manner. In a preferred embodiment, the hydroforming reaction mixtures that may be employed herein include any mixture derived from any corresponding hydrolysis process that contains at least a certain amount of four different major ingredients or components, ie, the aldehyde product, a metal-organophosphorus ligand catalyst,
free organophosphorus ligand and an organic ßalubi lization agent for said catalyst and said free ligand, said ingredients correspond to those employed and / or produced by the hydrofor lation process from which the initial material of the hydroformylation reaction mixture. It will be understood that the hydroformylation reaction mixture compositions employable herein may contain and usually contain minor amounts of additional ingredients such as, for example, those which have been deliberately employed in the hydroformylation process or formed in situ during said process. Examples of such ingredients that are also present include unreacted olefin starting material, carbon monoxide gases and hydrogen, as well as in situ formed type products, such as, for example, unreacted saturated and / or olefin and unreacted hydrocarbons that correspond to initial olefin materials, and liquid high-boiling aldehyde condensation byproducts, as well as other inert cosolvent-type materials or hydrocarbon additives, if used. The substituted or unsubstituted olefin reactants that can be employed in the hydroformylation processes (and other suitable processes) of this invention include both optically active olefinic unsaturated compounds
(prochirals and chirals) as well as non-optically active (achirals) containing from 2 to 40, preferably from 2 to 20 carbon atoms. Such unsaturated olefinic compounds can be terminally or internally unsaturated and have straight-chain, branched-chain or cyclic structures, as well as olefin mixtures, such as those obtained from the oligomerization of propene, butens, isabutene, etc. (such as that known as di-propylene, trimeric or tetrameric propylene and the like, as presented, for example, in U.S. Patent Nos. 4,518,809 and 4,528,403). In addition, such olefin compounds may additionally contain one or more unsaturated ethylenic groups and obviously mixtures of two or more different olefinic unsaturated compounds may be used as the starting material, if desired. For example, commercial alpha-olefins containing four or more carbon atoms may contain minor amounts of corresponding internal olefins and / or their corresponding saturated hydrocarbon and such commercial olefins do not necessarily need to be puri? Ed therefrom prior to their reaction. Illustrative mixtures of olefinicoß starting materials which can be employed in the hydroformylation reactions include, for example, mixed butenes such as for example Refined I and II. In addition such olefinic unsaturated compounds and products
The corresponding derivates therefrom may also contain one or several substituent groups which negatively affect the processes of this invention as described for example in US Patents Nos. 3,527,809, 4,769,498 and the like. More preferably, the present invention is especially useful for the production of non-optically active aldehydes, by the hydrolysis of achiral alpha-olefins containing from 2 to 30, preferably from 2 to 20 carbon atoms, and achiral internal olefin. containing from 2 to 20 carbon atoms, as well as mixtures of initial materials of taffe alfa alpha olefins and internal olefins. Illustrative internal olefins and olefinins include, for example, ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-nanene, 1-decene, 1-undecene, 1-dodecerta, 1-tridecene , 1-tetradecene, 1-pentadecene, 1-hexadecene, 1-heptadecene, 1-octadecene, 1-nonadecene, 1-eicosene, 2-butene, 2-meth i-propene (isobutylene), 2-methylobutene, 2- pentene, 2-ene, 3-hexene, 2-heptene, 2-octene, cyclohexene, propylene dimers, propylene trimers, propylene tetramers, butadiene, piperylene, isoprene, 2-ethyl-1-he? ene, styrene, 4-meti leßt i reno, 4-isoprapi les i reno, 4-tert-buti ireno, al fa-me i 1es treno, 4-tert-buti 1-alpha-me i lestireno, 1, 3- i isop apeni 1 benzene,
3-phenyl-1-propene, 1,4-he-adieno, 1,7-octadiene, 3-cyclohexyl-1-butene and the like, as well as 1,3-dienes, butadiene, alkyl alkenoates, for example pentenoate methyl, alkenyl alkanoates, alkyl alkenyl ethers, alkenoles, for example, pentenoles, alkenes, for example pentenales, and the like, such as, for example, 11 allyl alcohol, allyl butyrate, he? -l-en-4- ol, oct-l-en-4-ol, vinyl acetate, allyl acetate, 3-butenyl acetate, vinyl propionate, allyl propionate, methyl methacrylate, vinyl ethyl ether, vinyl methyl ester, ethyl ether of allyl, n-propyl-7-octenoate, 3-butenniyl, 5-heenamide, eugenol, ißo-eugenol, safrole, ißo-safrsl, anethole, 4-allantole, indene, lionene, beta-pinene , dicyclopentadiene, cyclooctadiene, ca pheno, linalool, and the like. Illustrative prochiral and chiral olefins useful in asymmetric hydropharmacy processes (and other asymmetric processes) that can be employed to produce mixtures of enantiomeric products that may be encompassed by this invention include those represented by the formula:
where Rl, R2, R3 and R4 ßon equals or differentß (provided
that Rl is different from R2 or R3 is a tooth of R4) and are selected from hydrogen; I rent; Substituted alkyl, said substitution is selected from dialkyl, such as benzylamino and tribenzylamino, alkoxy such as methoxy and ethoxy, acyloxy, such as acetoxy, halo, nitro, nitrile, thio, carbonyl, carbaxamide, carboxaldehyde, carb? xyl, carboxylic ester; aryl including phenyl; substituted aryl including phenyl, said substitution is selected from alkyl, amino including alkylamino and dialkylamino such as for example taenzylamino and dibenzylamino, hydroxy, alkoxy such as for example metho? i and ethoxy, acyl? i, such as acetoxy; halo, nitrile, nitro, carbóxila, carboxaldehydes, carboßl ether, ca boni la and tio; acyloxy co or for example acetoxy; alkoxy, such as, for example, methoxy and ethoxy; amino including alkylamino co or for example benzylane and dibenzylamino; acylamino and triacylamine, such as, for example, acetylbenzylamino and diacetylamino; nitro, carbopyla, nitrile, carbólaila; carboxamide; carba? aldehyde; carbo-yl ester; and alkyl mercapto as for example met i Imercapto; it is understood that the prochiral and chiral olefins of this definition also include molecules of the above general formula wherein the R groups are connected to form ring compounds, for example 3-meth i 1-1-cyclohexane, and the like. Optically active or prochiral olefin compounds
Illustrative useful in asymmetric hydroformylation processes (and other asymmetric processes) of this invention include, for example, p-isobutyl irene, 2-vinyl-6-methoxy-2-naphne, 3-ethenyl-phenyl-phenyl ketone, -eteni lfeni 1-2- ieni Icetona, 4-eteni 1-2-fluorobi feni lo, 4- (1, 3-dihydra-l-oxo-2H-isoindal-2-i 1) styrene, 2-eteni 1- 5-benzoyl-1-ene, phenyl ether of 3-etheni Ifeni 1, proeni lbencena, isobuti 1-4-propeni-benzene, phenyl vinyl ether and the like. Other olefinic compounds include substituate aryl ethylene in accordance with that described, for example, in U.S. Patent Nos. 4,329,507, 5,360,938 and 5,491,266, the disclosures of which are incorporated herein by reference. To illustrate suitable initial and unsubstituted olefinic starting materials we can mention the specific permissible substituted and unsubstituted olefinic compounds in Kirk-Othmer, Encyclopedia of Chemical Technology, Fourth Edition, 1996, the relevant parts of which are incorporated herein by reference . As noted, the hydroformylation processes of this invention involve the use of an organophosphorus metal-ligand complex catalyst in accordance with that described above. The metal-organophosphorus ligand catalyst is not subjected to any deactivation
in the presence of only carbon monomer and hydrogen and / or effect a change in normal selectivity of aldehyde of less than 0.2% normal aldehyde per 1 pound per square inch of partial pressure of carbon monoxide. The hydrofarmy lac ion catalysts can be in homogeneous form during the reaction and / or during the separation of products. And, of course, mixtures of such catalysts can be employed. The amount of metallo-organophosphorus ligand catalyst present in the reaction medium of a given hydrolysis process encompassed by this invention only requires to be the minimum amount necessary to provide the desired metal concentration desired to be employed and which will provide the basis for at least the catalytic amount of metal necessary to catalyze the particular hydroformylation process involved in accordance with what is presented, for example, in the aforementioned patents. In general, concentrations of metal, for example rhodium, within a range of about 10 parts per million to about 1000 parts per million, calculated as free rhodium, in the hydroformylation reaction medium must be sufficient for most processes. while it is generally preferred to employ from about 10 to 500 parts per million of metal, for example, rhodium, and more preferably from 25 to 400 parts.
per million metal, for example rhodium. In addition to the metal-organophosphorus ligand catalyst, free organophosphorus ligand (i.e., the ligand that does not complex with the metal) may also be present in the medium of the hydropharmacy reaction. The free organophosphorus ligand may correspond to any of the above defined organophosphorus ligands which may be employed herein. It is preferred that the free organophosphorus ligand be the same as the organophosphorus ligand of the metal-organophosphorus ligand catalyst employed. However, such ligands do not need to be the same in a given process. The hydroforming process of this invention can involve from about 0.1 mole or less to about 400 mole or more of free organophosphorus ligand per mole of metal in the hydroformylation reaction medium. Preferably, the hydroformylation process of this invention is carried out in the presence of about 1 to about 200 moles of organophosphorus ligand, and more preferably of organopolysoses, from about 1.1 to about 4 moles of phosphorus ligand. organopol i phosph ito per mole of metal present in the reaction medium; such amounts of organophosphorus ligand are the sum of the amount of bound organophosphorus ligand (which forms complexes) with the
metal present and the amount of free organophosphorus ligand (which does not form complexes) present. Since it is preferred to produce non-optically active aldehydes by the hydroformylation of olefins herein, the most preferred arganoforphosphorus ligands are achiral-type arganofβ-phosphorus ligand, especially those encompassed by Formula (I) above and more preferably those of Formulas (II) and (V) above. Obviously, if desired, additional organophosphorus ligand or decompensation can be delivered to the reaction medium of the hydroformylation process at any time and in any suitable manner, for example, to maintain a predetermined level of free ligand in the reaction medium. . The reaction conditions of the hydroformylation processes encompassed by this invention can include any suitable hydroformylation condition used hitherto for the production of optically active and / or non-optically active aldehydes. For example, the total gaß pressure of hydrogen, monomer carbon and initial olefin compound of the hydraformilation process can be located within a range of about 1 to about 10,000 pounds per square inch, absolute pressure. In general, however, it is preferred that the process operate at a total pressure of hydrogen gas, carbon monoxide and lower olefin starting compound
at about 2000 pounds per square inch, absolute pressure and more preferably less than about 500 pounds per square inch, absolute pressure. The minimum total pressure is predominantly limited by the amount of reagents needed to obtain a desired reaction rate. More specifically, the carbon monomer partial pressure of the hydropharmacy process of this invention is preferably from about 1 to about 1000 pounds per square inch, absolute pressure, and more preferably from about 3 to about 800 pounds. per square inch, absolute pressure, while the partial pressure of hydrogen is preferably from about 5 to about 500 pounds per square inch, absolute pressure and more preferably from about 10 to about 300 pounds per square inch, absolute pressure. In general, the H2: C0 molar ratio between gaseous hydrogen and carbon monomer can be within a range of approximately 1:10 to 100: 1 or more, the molar ratio between hydrogen and monoxide. preferred carbon is from about 1:10 to about 10: 1. In addition, the hydroforming process can be carried out at a reaction temperature of about -25 ° C to about 20 ° C. In general, reaction temperatures of hydrofarmy the ion of about 50ßC are preferred to
approximately 120 * C for all types of olefinic starting materials. Obviously, it will be understood that when non-optically active aldehyde products are desired, initial achiral-type olefin materials and organophosphorus ligands are used and when it is desired to obtain optically active aldehyde products, initial olefin materials of the prochiral type are used. well chiral desired and organophosphorus ligands. And it will also be understood that the hydroformylation reaction conditions employed will be governed by the type of aldehyde product desired. The hydrofarmylation processes encompassed by this invention are also carried out in the presence of an organic solvent for the metal-organophosphorus ligand catalyst and free arganophosphorus ligand. The solvent may also contain dissolved water up to the saturation limit. Depending on the reagents and the particular catalyst employed, suitable organic solvents include, for example, alcohols, alkanes, alkynes, alkynes, ethers, aldehydes, high-boiling aldehyde condensation byproducts, ketones, steres, amides, tertiary amines, aromatics and the like. Any suitable solvent that does not interfere in a negative manner with the predicted hydroformylation reaction can be employed and such solvents can include those presented up to and including
date commonly employed in hydroformylation reactions catalyzed by known metals. Mixtures of one or more different solvents can be used, if desired. In general, in connection with the production of (non-optically active) achiraleb aldehydes, it is preferred to employ aldehyde compounds corresponding to the desired aldehyde products to be produced and / or liquid high-boiling aldehyde condensation byproducts as major organic solvents as is common in the art. Such aldehyde condensation byproducts may also be pre-formulated if desired and used in a corresponding manner. Illustrative preferred solvents which may be employed in the production of aldehydes include ketanes (for example acetone and methyl ethyl ketone), steres (for example ethyl acetate), hydrocarbons (for example toluene), or trahydrocarbons (for example, no benzene), ethers (for example tetrahydrofuran (THF)), 1,4-butanediols and sulfolane. Suitable solvents are presented in U.S. Patent No. 5,312,996. The amount of solvent employed is not a critical factor for the present invention and it is only required that it be an amount sufficient to solubilize the catalyst and free ligand of the hydroformylation reaction mixture to be treated. In general, the amount of sun can be located within a range of
about 3% by weight to about 99% by weight or more based on the total weight of the initial material of the hydroformylation reaction mixture. Accordingly illustrative non-optically active aldehyde products include, for example, propionaldehyde, n-buraldehyde, isobutyraldehyde, n-valeraldehyde, 2-methyl-1-buraldehyde, hexanal, hydroheta-anal, 2- and i-1alderaldehyde, heptanal, 2-methyl-1-he-anal, octanal, 2-methyl-1-heptanal, non-nal, 2-methyl-1-octanal, 2-ethyl-1-heptanal, 3-propyl-1-hexanal, decanal, adipaldehyde, 2 - et i lglutaraldehldo, 2-meti ladipaldehyde, 3-methylapaaldehyde, 3-hydroxypropionaldehyde, 6-hydroxyhexanal, alkenes such as 2-, 3- and 4-pentenal, alkyl 5-formi 1 alerata, 2-me i 1- 1-nonanal, undecanal, 2-methyl-1-decanal, dodecanal, 2-methyl-1-undecanal, tridecanal, 2-methyl-1-tridecanal, 2-ethyl, 1-dodecanal, 3-propi 1-1-undecanal, pentadecanal, 2-methyl-l-tetradecanal, he? Adecanal, 2-methyl-1-1-pentadecapal, heptadecanal, 2-methyl-1-hexadecanal, octadecanal, 2-methyl-1-heptadecanal, nonodecanal, 2-methyl-1 -octadecan l, 2-ethyl-l-heptadecan l, 3-prapi 1-1-hexadecana 1, e icosanal, 2-meti 1-1-nonadecanal, heneicosanal, 2-meti 1-1-eicosanal, tricosanal, 2-me i 1-l-docosan l, tetracosanal, 2-met i 1-1-tricosanal, pentacosapal, 2 -met i 1-1-tetracosanal, 2-ethyl 1-tricosanal, 3-propi 1-1-docosanal, heptacosanal, 2-me i 1-1-oc acos nl,
nonacosanal, 2-meti 1-1-actacosanal, hent iacontanal, 2- et il-1-triacontanal, and the like. Illustratively active aldehyde products include aldehyde compounds (enantomeric) prepared by the asymmetric hydropharmacy process of this invention as for example S-2- (p-isobut i 1 fep 1) -propionaldehyde, S-2 - (6-methoxy-2-naph i 1) prop ianaldenido, S-2- (3-benzoi lfeni 1) -propionaldeh gone, S-2- (pt ienoi Ifeni 1) propionaldehyde, S-2- (3 -fluoro-4-pheni 1) phenyl Ipropionaldehyde, S-2- (4- (l, 3-dihydro-l-oxo-lH-ißindol-2-yl) phenyl) propisnaldehyde, S-2- (2-methylacetalden id) -5-benzoyl-1-thiamphen and the like. Suitable exemplified substituted and unsubstituted aldehyde products include the permissible substituted and unsubstituted aldehyde compounds described in irk-Othmer, Encyclopedia af Chemical Technology, Fourth Edition, 1996, the relevant parts of which are incorporated herein by reference . As indicated above, it is generally preferred to carry out the hydroformylation processes of this invention in a continuous manner. In general, continuous hydroformylation processes are well known in the art and can involve: (a) hydroformylation of the olefinic material or starting materials with carbon monoxide and hydrogen in a homogeneous liquid reaction mixture that
Cf?
it comprises a solvent, the organophosphorus metal-ligand complex catalyst, and free organophosphorus ligand; (b) maintaining the reaction temperature and favorable pressure conditions for the hydroformylation of the olefinic material or starting materials; (c) supply compensation amounts of the olefinic material or initial materials; carbon monoxide and hydrogen to the reaction medium as these reagents are depleted; and (d) recovering the lac hydraform product (s). aldehyde ion deeeadoß in a desired manner. The continuous process can be carried out in a single pass mode, ie, where a vapor mixture comprising the unreacted olefinic material or starting materials and vaporized aldehyde product is removed from the liquid reaction mixture from wherein the aldehyde product is recovered and the initial olefinic compensating material, carbon monoxide and hydrogen are supplied to the liquid reaction medium during the next single passage without recycling of the unreacted olefinic starting material or materials. Such types of recycling process are well known in the art and may involve liquid recycling of the metal-organophosphorus ligand catalyst mixture separated from the desired aldehyde reaction product (s) as presented, for example, in United States Patent No.
4,148,830 or a gaß recycling process in accordance with that presented, for example, in US Patent No. 4,247,486, as well as a combination of both liquid and gas recycling procedures if desired. The disclosures of said US Patents Nos. 4,148,830 and 4,27,486, are incorporated herein by reference. The most preferred hydroformylation process of this invention comprises a continuous liquid catalyst recycling process. Suitable liquid catalyst recycling processes are presented, for example, in U.S. Patent Nos. 4,668,651; 4,774,361; 5,102,505 and 5,110,990. In one embodiment of this invention, the aldehyde product mixtures can be separated from the other components of the crude reaction mixtures in which the aldehyde mixtures are produced by any suitable method. Suitable methods of separation include, for example, solvent extraction, phase separation, crystallization, distillation, vaporization, evaporation on rubbed film, descending film evaporation and the like. It may be desirable to remove the aldehyde products from the crude reaction mixture as they are formed by the use of entrapment agents in accordance with that described in Patent Application of the Patent Cooperation Treaty published W0 88/08835. A preferred method for
Separation of the aldehyde mixtures from the other components of the crude mixtures of the reaction is by membrane separation. Such membrane separation can be achieved in accordance with that presented in U.S. Patent No. 5,430,194 and the corresponding North American Patent Application Na. of Series 08 / 430,790, filed on May 5, 1995, mentioned above. As indicated above, at the end of the process of the invention (or during said process) the desired aldehydes can be recovered from the reaction mixtures used in the process of this invention. For example, the recovery technique presented in U.S. Patents Nos. 4,148,830 and 4,247,486 may be employed. For example, in a continuous liquid catalyst recycling process, the part of the liquid reaction mixture (containing aldehyde product, catalyst, etc.), that is, the reaction mixture, removed from the reaction zone can be transferred to a separation zone, for example, vaporizer / separator, where the desired aldehyde product can be separated by distillation, in one or several steps, under normal, reduced or elevated pressure, from the liquid, condensed and liquid reaction mixture. collected in a receptacle for product, and further purified if desired. The remaining volatilized catalyst containing the liquid reaction mixture can then be recycled from
new to the reaction zone as, if desired, any other volatile material, for example, unreacted olefin, together with hydrogen and mono? The carbon dioxide is dissolved in the liquid reaction after removal of the condensed aldehyde product, for example, by distillation in any conventional manner. In general, it is preferred to separate the desired aldehydes from the reaction mixture containing ba catalyst or reduced pressure and at low temperatures in order to avoid possible degradation of the arganophosphorus ligand and reaction products. When an alpha-mono-olefin is used as the reactant, the derivatized aldehyde can also be separated by the above methods. More particularly, the distillation and separation of the desired aldehyde product from the meta-1-organ complex catalyst catalyst forum containing the reaction mixture can be carried out at any desired suitable temperature. In general, it is recommended that said distillation be carried out at relatively low temperatures, such as 150 ° C, and more preferably at a temperature in the range between about 50 ° C and about 140 ° C. It is also generally recommended that said distillation of aldehyde be carried out under reduced pressure, for example, a total gas pressure substantially less than the total pressure of
gas used during hydroforming when low-boiling aldehydes are involved (eg C4 to C6> or under vacuum when high-boiling aldehydae are involved (eg C7 or more) For example, a common practice is subjecting the liquid reaction product medium removed from the hydroformylation reaction zone to a reduction in pressure in order to volatilize a substantial part of the undigested gases in the liquid medium which now contains a much lower concentration of Synthesis gas from what was present in the hydroformylation reaction medium to the distillation zone, eg vaporizer / separator, where it is distilled in desired aldehyde product In general, distillation pressures within a range of vacuum pressures up to a total gas pressure of approximately 50 pounds per square inch read on the gauge should be sufficient for most of the pr opposites For the purposes of this invention, the term "hydrocarbon" encompasses all permissible compounds having at least one hydrogen and one carbon atom. In a broad respect, perishable hydrocarbons include aromatic and non-aromatic, carbocyclic and heterocyclic, branched and unbranched, acyclic and cyclic organic compounds that may be substituted or not substituted. tuidoß.
As used herein, the term "its contents" encompasses all perishable substitutes of organic compounds unless otherwise indicated. In a general aspect, the permissible substituents include their aromatic and nonaromatic, carbocyclic and heterocyclic, branched and unbranched, acyclic and cyclic components of organic compounds. Illustrative examples include, for example, alkyl, alkyloxy, aryl, aryloxy, hydroxy, hydroxyalkyl, amino, to inaalkyl, halogen, and the like wherein the number of carbons may be within a range of 1 to about 20 or more preferably from 1 to appro? imadamente 12. Permissible substitutes can be one or more and can be the same or different for appropriate organic compounds. This invention is not intended to be limited in any way by the permeable substitutes of organic compounds. Some of the following examples are provided to further illustrate this invention. EXAMPLE 1 A single reactor vessel with reaction reaction stage was used for ethylene hydroformy in propionaldehyde. The container was divided into three stages by horizontal physical barriers. The reagents were all fed in the reaction and bottom stage and advanced vertically upwards through the vessel. The background portion
of the container represented 3% of the volume available for hydroformylation. The middle portion of the container represented 28% by volume, and the upper portion of the reactor represented the remaining volume available for the reaction. The vessel was equipped with an agitator mounted on the top of the vessel to provide agitation within each individual stage of the reaction. The catalyst employed in the hydroformylation consisted of 107 parts per million of rhodium or radio metal, 3.8% by weight of triphenylphosphine, and 31.5% by weight of propionaldehyde condensation product, and the remainder of the catalyst consisted of propionaldehyde, non-converting reagents, and other hydroformy by-products with, for example, ethane. Reagent feed rates to the reactor vessel expressed as cubic feet per hour per cubic foot of total volume of hydroformylation of ethylene, hydrogen and carbon monoxide were 97.8 cubic feet of ethylene / cubic foot of hydroformylation volume. hour, 106.2 cubic feet of hydrogen / cubic feet of hydroformylation volume / hour, and 102.8 cubic feet of carbon monoxide / cubic feet of hydroformy volume / hour, respectively. Inert substances that represented up to 3.8 cubic feet / cubic feet of hydroformylation volume / hour were also fed to the reactor with the feed (
standard conditions for this example are 32 ° F 1 atm? sfera). Hydroformylation was carried out at a temperature of 88 ° C in the background compartment, 86 ° C in the middle compartment and 83 ° C in the ßuperiate compartment. The total reaction of the reaction vessel was 275 pounds per square inch, absolute pressure. The partial pressures resulting in vapor venting from the top of the reactor for ethylene, hydrogen and carbon oxide were 1.5 litas per square inch, 127 lb per square inch and 77 pounds per square inch, respectively. The overall reaction rate in propionaldeh reached was 4.2 gmol / L / hour. The product was separated from the catalyst and the concentrated catalyst was recycled to the reactor vessel in destions. Example 2 A hydroformylation system with 350 parts per million in rhodium metal binder, 20% by weight triphenylphosphine, 50% in butyric acid butyric acid, and the remainder of the solution consisting of aldehyde condensation byproducts, other byproducts of reaction or reactants, provides the percentage changes of the hydroformylation regime in relation to the partial pressure of carbon monoxide in accordance with that presented in Table A below. The partial pressures of the other reagents are 100
pounds per square inch of prapilena, 50 pounds per square inch of hydrogen, and the value for the partial pressure of carbon monoxide ee provided in Table A. The temperature of the reaction is 100ßC. The reaction pressure is at least the total partial pressures of the reactants. Table A Partial Pressure of CO, Percentage change of pounds per square inch hydroformy reaction 3.5 13.6 5.5 8.1 7.5 5.4 9.5 3.8 29.5 0.4 Even though the invention has been illustrated through some of the previous examples, said invention does not is limited to these examples; on the contrary, the invention covers the generic area presented here. Various modifications and modalities can be made without departing from the spirit or scope of the present invention.
Claims (14)
- CLAIMS 1. A process for producing one or more products in a reactor in stages that has more than one reactive stage, said process comprises the reaction in said reactor in stages of one or several reactants with carbon monoxide in the presence of a complex catalyst. metal-organophosphorus ligand and optionally free organophosphorus ligand to produce said product or said products, wherein said metal-organophosphorus ligand catalyst is not subjected to a β-substantial deactivation in the presence of only carbon monoxide and / or causes a change in selectivity of normal product below 0.2% of normal product per one pound per square inch of partial pressure of carbon monoxide.
- 2. A process of hydroformylation to produce one or more aldehydes in a reactor in stages having more than one reactive stage, said process comprises the reaction in said reactor in stages of one or several alephine compounds unsaturated with carbon monoxide and hydrogen in the presence of a metal-organophosphorus ligand catalyst and optionally free organophosphorus ligand to produce said aldehyde or said aldehydes, wherein said organophosphorus metal-1-organ complex catalyst is not subject to substantial deactivation in the presence of only carbon monoxide and hydrogen and / or causes a change in selectivity of normal aidehyde less than 0.2% normal aldehyde per one pound per square inch of partial monoclonal carbon prehesion.
- 3. A process for producing one or more products in a reactor in stages having more than one reactive stage, said process comprising reacting said reactor in stages of one or several reagents with monomer carbon in the presence of a catalyst of metal-1 igand organophosphorus complex and optionally free organophosphorus ligand to produce said product or said products, wherein said metal-1 igand organophosphorus complex catalyst is not subject to a substantial deactivation in the presence of only monoxide carbon and / or causes a change in normal product selectivity of less than 0.2% of normal product per one pound per square inch of partial pressure of carbon monoxide and / or causes a change in reaction rate of less than 2% per pound per square inch of partial pressure of carbon monoxide.
- 4. A hydroformylation process for producing one or more aldehyde-β in a reactor in step e having more than one reactive step, said process comprising reacting in said reactor in stages one or more olef-trick compounds unsaturated with carbon monoxide and hydrogen in presence of a metal-organophosphorus ligand catalyst and optionally free organophosphorus ligand to produce said aldehyde or said aldehydes, wherein said metal-organophosphorus ligand catalyst is not subjected to a substantial degradation in the presence of only carbon monoxide and hydrogen and / or causes a change in selectivity of normal aldehyde lower than 0.2% normal aldehyde per pound per square inch of partial pressure of carbon monoxide and / or causes a change in reaction rate of less than 2% per pound per square inch of partial pressure of carbon monoxide.
- 5. The processes of the re-indications 1, 2, 3 and 4 in which the reactor in stage comprises: a reactor device oriented in a substantially vertical manner; a stirring device within said reactor die, said stirring device is associated with the said reactor device and comprises an elongated rod device having a plurality of blades placed around said rod device, said device agitation ß extends ßubßtancialmente throughout the length of said reactor device; at least two reagent input devices in the lower part of said reactor device for continuously transporting one or more olefinic compounds, one or more metal-organophosphorus ligand catalysts and a source of hydrogen and carbon monoxide in said device reactor; At least one reagent entry device at the top of said reactor device for continuously conveying one or several olefinic compounds, one or more metal-organophosphorus ligand catalysts and / or a source of hydrogen and monoxide. carbon in said reactor diepoeitive; at least one product outlet device on top of said reactor device for continuously removing product, organophosphorus metal complex-ligand catalyst and unreacted reactants from said reactor device; and at least one deflection device on the internal surface of said reactive device; said deflection device is spaced such that said deflection device is interleaved between said blade of said agitation device. 6. The processes of the re-indication 5 wherein the staged reactor further comprises a heat removal device comprising an external loop and / or internal coils. 7. The processes of claims 1, 2, 3 and 4 in which the reactor in stages comprises: a container oriented substantially vertically; a plurality of generally horizontal deviators placed within said container and dividing the part internal of said container in a plurality of chamber, each of said diverters form with a central hole and is mounted on the external wall of said container; at least two input diphosphate to feed one or more olefinic compounds, one or more catalysts of complex metal-1 igand of organophosphorus and a source of hydrogen and carbon monoxide in one or more lower chambers; optionally at least one input device for feeding one or more olefinic compounds, one or more catalyst catalysts of metal-organophosphorus ligand complex and / or a source of hydrogen and carbon monoxide in one or more upper chambers; at least one ßalide device for removing hydrofarmizing compounds, metal-organophosphorus ligand catalysts and unreacted reagents from one or more lower chambers; a generally vertical rotating drive shaft centrally pivoted to rotate in said container and generally extending concentrically through each of said holes in each of said diverters; and a plurality of drivers each mounted to rotate in said shaft and generally positioned above or below each of said holes of said horizontal deviators, said impeller has a size in relation to said holes ß sufficient to provide for the mixing of said hydroformylation reagents ion, catalysts organophosphorus metal-ligand complex and products as they move from a lower chamber upwards to an adjacent chamber where said hydroformylation reagents, metal-1 complex organophosphorus catalysts and products are mixed well within each chamber. 8. The processes of the re-indication 7 in which the staged reactor further comprises a dispoeiti or heat removal comprising an external loop and / or internal coils. 9. The processes of the re-indications 1, 2, 3 and 4 in which the stage reactor comprises: a vertical cylindrical vessel with a plurality of stationary horizontal non-perforating deviators spaced apart that divide said vessel into superimposed compartments, said diverters have central openings for communication between said compartments; an upright flange placed around the circumference of the central opening of each compartment; a shaft mounted rotatably axially in relation to said container and extending through said compartments and a stirring device for the shaft; a device for admitting carbon monoxide, hydrogen, one or more metal-ligand-orgapphosphorus ligand catalysts and one or more olefinic compounds in the lower end compartment; and a device for removing product aldehyde, catalyst-metal complex-organophosphorus ligand and unreacted reagent from the upper end compartment. The processes of claims 1, 2, 3 and 4 in which the step-stage reactor comprises: a container with a generally cylindrical elongated chamber within said container; an agitator shaft which extends coaxially through the chamber, the shaft extends towards the outside of the chamber and is equipped with a device for impuing it; a plurality of transverse divisions in the chamber open in their centers around the agitation tree that divide the camera into a linear series of compartments in open communication between them; an agitator to provide an essentially complete back-mixing in each compartment; vertical deflectors in each compartment that project radically towards the center to prevent the swirling of the fluids being agitated, designed to produce in each compartment when the agitator turns a cylindrical flow of fluid and gas from the periphery of the agitator towards the peripheral wall of the chamber, consequently along the chamber in each direction along the walls of the frame, and consequently radially adjacent inwardly of said divisions towards the shaft; a device for the entry of carbon monoxide, hydrogen, one or more catalysts of metal complex-organophosphorus ligand and one or more olefinic compounds in the lower end compartment; and a diβpositive to remove aldehyde product, metal-organophosphorus ligand complex catalyst and ßin-converting reagents from the upper end compartment. 11. The processes of the rei indicate ioneß 1, 2, 3 and 4 in which the reactive stages are physically separated by deflection plates with passage from reactive stage to reactive stage where said ßon paßajeß such that the backflow of gas is minimized and liquid. 12. The processes of the indications 1, 2, 3 and 4 in which the stages are reactivated and separated by differentiated mixing patterns that create regions of various concentrations and allow the gas and liquid to flow from reactive stage to reactive stage. 13. Procedures in accordance with lae rei indications 1 and 3 comprising a process of hydroformylation, hydroacylation (intramolecular and intermolecular), hydration, hydrosterification or carbonylation. 14. The proceeds of the rei indications 1, 2, 3 and 4 wherein said orgapphosphorus metal-ligand complex catalyst comprises rhodium forming complexes with an organophosphorus ligand having the formula selected from: (i) a triorgano ligand osf ina represented by the formula: where R 1 is the same or different and represents a substituted or unsubstituted monovalent hydrocarbon radical which has from 1 to 24 carbon atoms or more; (ii) a monoorganosphosphine represented by the formula: OR where R3 represents a substituted or unsubstituted trivalent hydrocarbon radical containing from 4 to 40 carbon atoms or more; (iii) a diorganophosphite represented by the formula where R 4 represents a divalent or unsubstituted hydrocarbon radical containing from 4 to 40 carbon atoms or more and W represents a substituted or unsubstituted monovalent hydrocarbon radical containing from 1 to 18 carbon atom or more; (iv) a triorganophosphite represented by the formula: wherein each R8 is the same or different and represents a substituted or unsubstituted monovalent hydrocarbon radical; and (v) an organophobia containing two or more tertiary phosphorus atoms (trivalent) represented by the formula: where XI represents a valence hydrocarbon bridge of "n" substituted or unsubstituted valence containing from 2 to 40 carbon atoms, each R9 is the same or different and represents a divalent hydrocarbon radical containing from 4 to 40 carbon atoms. Each RIO is the same or different and represents a substituted or unsubstituted monovalent hydrocarbon radical containing from 1 to 24 carbon atoms, "a" and "b" may be the same or different and each has a value from 0 to
- 6. , provided that the sum of "a + b" is 2 to 6 and "n" is equal to "a + b".
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US008289 | 1995-12-06 | ||
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US08757743 | 1996-11-26 | ||
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US08/757,743 US5728893A (en) | 1995-12-06 | 1996-11-26 | Process using multistaged reactors |
US008,289 | 1996-11-26 |
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MXPA98004284A true MXPA98004284A (en) | 1999-01-11 |
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MX9804489A MX203409B (en) | 1995-12-06 | 1998-06-05 | Improved metal-ligand complex catalyzed processes |
MX9804494A MX9804494A (en) | 1995-12-06 | 1998-06-05 | Processes employing indicator ligands |
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MX9804494A MX9804494A (en) | 1995-12-06 | 1998-06-05 | Processes employing indicator ligands |
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- 1996-12-05 WO PCT/US1996/019313 patent/WO1997020793A1/en active IP Right Grant
- 1996-12-05 DE DE69611765T patent/DE69611765T2/en not_active Revoked
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1998
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