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WO1991008196A2 - Procede de preparation d'arylethanolamines a partir de precurseurs d'aminocarbinol - Google Patents

Procede de preparation d'arylethanolamines a partir de precurseurs d'aminocarbinol Download PDF

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Publication number
WO1991008196A2
WO1991008196A2 PCT/US1990/006511 US9006511W WO9108196A2 WO 1991008196 A2 WO1991008196 A2 WO 1991008196A2 US 9006511 W US9006511 W US 9006511W WO 9108196 A2 WO9108196 A2 WO 9108196A2
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Prior art keywords
resin
formula
alkyl
compounds
hydrogen
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Application number
PCT/US1990/006511
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English (en)
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WO1991008196A3 (fr
Inventor
Sami Y. Kalliney
Mariano V. Ruggeri
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Schering Corporation
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Publication date
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Publication of WO1991008196A2 publication Critical patent/WO1991008196A2/fr
Publication of WO1991008196A3 publication Critical patent/WO1991008196A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton

Definitions

  • Arylethanolamines are compounds which have been discovered as having properties useful in treating hypertension, as taught in Ireland Patent Specification 31391 filed 19 September 1967 and J.E. Clifton, I. Collins, P. Hallett, D.H. Hartley, L.H.C. Lunts and P. D. Wicks, Arylethanolamines Derived from Salicylamide with ⁇ - and ⁇ - Adrenoceptor Blocking Activities; Preparation of Labetalol, its Enantiomers, and Related Salicylamides, J. Med. Chem. 25, pp. 670-679 (1982).
  • Labetalol is a particular arylethanolamine used for treating hypertension, and is classified as both and ⁇ - and ⁇ - adrenergic blocker.
  • Dilevalol is the (R,R) enantiomeric form of labetalol.
  • Methods for preparing such compounds are taught in U.S. Patents 4,066,755 and 4,012,444 to Lunts et al., U.S. 4,658,060 to Gold et al., and to D. Hartley, Asymmetric and stereoseiective synthesis of arylethanolamines, Chemistry and Industry, 15 August 1981 , pp. 551-556.
  • Gold et al. further teach that the (R,R) arylethanolamine isomer (ie.
  • dilevalol possesses high ⁇ -1 blocking activity.
  • United Kingdom Patent Specification 1 ,024,914 discloses a process for the production of racemic napthalene derivatives from corresponding optically active compounds using mineral acids such as hydrochloric acid.
  • the present invention is directed to a process for preparing a racemic mixture containing approximately equimolar amounts of stereoisomers of the formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aromatic heterocyclic or substituted aromatic heterocyclic, with the proviso that R 1 is not hydrogen, alkyl or substituted alkyl, and R 1 can also represent the salicylamide moiety:
  • R 7 , R 8 and R 9 independently represent any of the values for R 1 ,
  • the present process comprises the steps of
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined hereinbefore, with a strongly cationic exchange resin;
  • R 1 is the salicylamide moiety:
  • step (a) further comprises the steps of (a1) contacting, in the presence of a solvent, the compound of formula II with the cationic exchange resin; (a2) separating the solvent from the cationic exchange resin prior to heating the resin. More preferably, the process comprises the additional step of, (a3) washing the resin with water or with acidified water prior to heating.
  • the present invention has the advantage of concentrating and purifying stereoisomers of formula II from an effluent stream while concommittantly converting one of the stereoisomers to the desired stereoisomeric form.
  • alkyl refers to a straight chain saturated hydrocarbon moiety containing from 1 to 10 carbon atoms, or a branched saturated hydrocarbon moiety of 3 to 10 carbon atoms, such as for example, methyl (i.e. -CH3), ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like;
  • substituted alkyl refers to an alkyl moiety which is further substituted at a carbon by one or more of the following groups: halo, alkyl of one to ten carbon atoms, aryl of six to fifteen carbon atoms, cyano (i.e. -CN), carboxyl (i.e. - COOH) or salts thereof, nitro (i.e. -NO2) and hydroxyl;
  • alkenyl refers to a straight hydrocarbon moiety of two to six carbon atoms or a branched hydrocarbon moiety of two to six carbon atoms having at least one carbon to carbon double bond such as allyl, ethenyl, propenyl, 1-butenyl, 2- butenyl, isobutenyl, 1 -pentenyl, 2-methyl-1 -butenyl, 1 -hexenyl and the like.
  • aryl refers to a carbocyclic moiety containing at least one benzenoid-type ring, with the aryl groups preferably containing from 6 to 15 carbon atoms, for example, phenyl, naphthyl, indenyl, indanyl and the like; the term “substit ited aryl” refers to an aryl moiety which is further substituted at a carbon by one or more of the following groups: halo, alkyl of one to six carbon atoms, aryl of six to fifteen carbon atoms, cyano (i.e. -CN), carboxyl (i.e. -COOH) or salts thereof, nitro (i.e.
  • aralkyl refers to an aryl moiety of six to 15 carbon atoms covalently bonded to an alkyl moiety of one to six carbon atoms, for example, benzyl, phenylethyl, and the like;
  • substituted aralkyl refers to an aralkyl moiety which is further substituted at the carbon by one or more of the following groups: halo, alkyl of one to six carbon atoms, aryl of six to fifteen carbon atoms, cyano (i.e. -CN), carboxyl (i.e. -COOH) or salts thereof, nitro (i.e.
  • aromatic heterocyclic refers to a cyclic moiety having at least one oxygen (O), sulfur (S) and/or nitrogen (N) heteroatom interrupting the ring structure and having a sufficient number of unsaturated carbon to carbon bonds, nitrogen to carbon bonds, and the like, to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, for example, 2-, 3- or 4- pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thioazolyl, 2- , 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6[1 ,2,4-triazinyl], 3- or 5-[1 ,2,4- thiadiazolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyi, 2-, 3-, 4-, 5- , 6- or 7-ind
  • heterocyclic alkyl refers to an aromatic heterocyclic moiety of 2 to 14 carbon atoms as defined hereinbefore, covalently bonded to an alkyl moiety of one to six carbon atoms
  • substituted heterocyclic alkyl refers to a heterocyclic alkyl moiety which is further substituted at a carbon or heteroatom by one or more of the following groups: halo, alkyl of one to six carbon atoms, aryl of six to fifteen carbon atoms, cyano (i.e. -CN), carboxyl (i.e.
  • Such resins are characterized by containing the sulfonic acid group (-SO3H), or phosphoric (-H2PO3 or -H2PO2) whose proton is readily ionizable in water, as compared to more weakly ionizable groups, such as carboxyl or phenolic groups.
  • sulfonic acid group -SO3H
  • phosphoric -H2PO3 or -H2PO2
  • the hydrogen capacity of the resin can range from about 0.3 to about 2.2 milliequivalents (meq) hydrogen per milliliter (ml) of wet resin, preferably from about 1.1 to about 2.0.
  • the hydrogen capacity otherwise known as the cation exchange capacity, is defined as the equivalent amount of hydrogen protons that can be held per volume of wet resin on a weight basis, typically in meq hydrogen per ml wet resin.
  • the resin employed should be aqueous saturated, ie. wet and in the hydrogen form.
  • Such cation exchange resins should also possess the appropriate degree of crosslink ⁇ ng.
  • Crosslinking is defined as the percent to which the chains of the resin polymers are bridged by elements, groups or compounds which join certain carbon atoms of the chains by primary chemical bonds.
  • the strong cationic exchange resin should be crosslinked to a percentage effective to effect racemization of the compounds of formula II, and should possess preferably from about 2 to about 12 percent (%) crosslinking, more preferably from about 4 to about 6%.
  • Commercially available strong cationic exchange resins include Dowex XFS-43279(H) and Amberlite IR 120 resins.
  • Dowex XFS-43279(H) ion exchange resin is a sulfonated copolymer of styrene and divinylbenzene in the hydrogen form, having a wet volume capacity of 1.22 meq/ml, a water retention capacity 66 percent, a pH of 3.5 and a particle size characterized by a Volume Median of about359 microns, a + 40 mesh of 0.5 percent, a -40/+50 mesh of 99.4 percent and a -50 mesh of 0.1 percent.
  • Dowex® strong cation exchange resins can be obtained from the Dow Chemical Company, Midland, Michigan U.S.A. 48667.
  • Amberlite strong cationic exchange resins can be obtained from the Rohm & Haas Co., Independence Mall West, Philadelphia, Pennsylvania, U.S.A. 19105. Conventional methods for utilizing such resins are taught in F.X. McGarvey, Introduction to Industrial Ion Exchange, Sybron Chemical Inc., Birmingham, New Jersey, IONAC® ion exchange resins, 11 pp.
  • the stereoisomer of formula II can be either in the R or in the S enantiomer form or in an optically active mixture thereof; preferably the S form.
  • the compound(s) of formula II should not be in a racemic mixture, as such mixture is the objective of the present invention.
  • R 4 , R 5 and R 6 are independently different substituents forming an optically active center.
  • R 4 is hydrogen
  • R 5 is phenylethyl
  • R 6 is methyl
  • a second chiral center will be present at the above moiety in the compounds of formula II.
  • One feature of the present invention is that the present process will not cause the inversion of the second chiral center if none of R 4 , R 5 and R 7 are hydroxyl.
  • the stereoisomer of formula (II) can be contacted with the strong cationic exchange resin to about 1 to 70 percent of the hydrogen capacity of the resin, preferably from about 40-60 percent, most preferably from about 50-60%.
  • the strong cationic exchange resin can be contacted per one meq resin, preferably from about 0.4-0.6 meq. compound formula II per one meq. resin, most preferably from about 0.5-0.6 meq. compound of formula II.
  • the solvent employed in the present invention can be from a general class of polar solvents capable of dissolving or suspending the compound of formula II.
  • DMSO dimethyl sulfoxide
  • water is one of the solvents, such as alcohol and water or dimethyl sulfoxide and water.
  • Water alone can be advantageous employed where the resin is in the hydrogen form or partially in the hydrogen form.
  • the process can be conducted neat i.e., in the absence of a solvent.
  • the solvents can be filtered off, the resin washed with water of acidified water, and then heated.
  • the resin containing the compound of formula II can be heated to a temperature effective to convert the compound of formula II to the racemic mixture of formula I.
  • Such temperatures can range from about 25 to about 100 degrees Celsius (°C), preferably from about 60 to 90°C, most preferably from about 80 to 85°C.
  • the heating is preferably conducted under inert conditions, ie. steam heating to exclude oxygen from the resin and the reaction medium.
  • the racemic compounds of formula I can be recovered by eluting the compounds from the resin with a suitable eluant.
  • suitable eluants include non-aqueous bases such as potassium t- butoxide and sodium methoxide.
  • the base can be a strong base having a pK 1 greater than the pK 1 of the aminocarbinol of formula (I), generally a pK 1 of 2 or greater.
  • the base can be an alkali metal carbonate such as sodium, potassium, lithium or cesium carbonate; hydroxides such as ammonium, sodium or potassium hydroxide, preferably NaOH.
  • the base can also be ammonia (NH3) or an organic base including urea; a secondary amine such as dimethylamine, diphenylamine, N-methyl,N-propylamine, diethylamine, diisopropylamine, N-methylaniline, piperazine, piperidine, pyrrolidine; or a tertiary amine such as trimethylamine, dimethylaniline, N,N-dimethylpropylamine, N,N- dimethylpiperidine, N,N-diethylbutylamine, triethylamine and tetramethylguanidine.
  • a secondary amine such as dimethylamine, diphenylamine, N-methyl,N-propylamine, diethylamine, diisopropylamine, N-methylaniline, piperazine, piperidine, pyrrolidine
  • a tertiary amine such as trimethylamine, dimethylaniline, N,N-dimethylpropylamine, N,N- di
  • the base can also be an heterocyclic nitrogen containing compound such as isoquinoline, morpholine, purine, pyridine, pyrazine, pyrimidine, quinoline or polyvinyl pyridine. Where appropriate, mixtures of any of the above bases can be employed.
  • the eluted resin can be regenerated by conventional procedures such as treatment by mineral acid, and reused for further reaction.
  • the eluted racemic mixture can then be purified by crystallization, solvent extraction and the like.
  • the aqueous media need not be removed prior to heating of the resin.
  • the organic solvent is separated from the resin containing the absorbed optically active material prior to heating the resin.
  • the racemic mixture of formula II thus recovered can be used to prepare more of the desired enantiomer. For example, if one uses the starting material of formula (II) which is predominantly the optically active S enantiomer and which possesses low pharmacological activity, the present process will partially convert some of the S enantiomer to the desired corresponding R enantiomer in approximately an equimolar ratio.
  • the present process provides an enriched racemic mixture containing about equimolar amounts of the S and the desired R enantiomer which possesses higher pharmacological activity.
  • the desired R enantiomer thus prepared can be separated from the racemic mixture by appropriate resolution of the racemic mixture by conventional procedures, such as crystallization, chiral chromatography and reaction with other optically active substrates as described in Clifton et al, supra, and in Paul Newman, Optical Resolution Procedures for Chemical Compounds, A publication of the Optical Resolution Information Center, Manhattan College, Riverdale, New York 10471 , Volumes 1 , 2, 3 and 4 (1984), whose preparative teachings are incorporated herein by reference.
  • the following examples illustrate the present invention in a manner of which it can be practiced but, as such, should not be construed as limitations upon the overall scope of the same.
  • the resin is successively washed with one bed-volumes of n- butanol, water, twice with five percent sulfuric acid and water at the above temperatures.
  • the water-resin mixture is heated to a temperature between about 89°C to 93°C under nitrogen for two hours, and cooled below 50°C
  • One hundred ninety five kilograms of 50 percent (weight per volume basis) NaOH is added to the resin together with 122 liters of n-butanol, the mixture is agitated for one hour, the eluant is removed.
  • the resin is retreated with NaOH and n-butanol in a second cycle and the recovered eluates are combined. Analysis indicates that the eluates contain 80 kg of the title compound in the titled (RR:SR) enantiomeric ratio.
  • the watered resin is heated to a temperature of 80°C for 5 hours under nitrogen, eluted three times with 250 ml of 2 molar (M) NaOH and 250 ml n-butanol, and the eluates are combined. Analysis indicates that the eluates contain the title compound in an enantiomeric ratio (RR:SR) of (1 :1).
  • the column is washed with one liter of n-butanol followed by one liter of hot water, which is continuously recycled through the column for four hours.
  • the temperature at the top of the column is maintained at about 83°C a d the temperature of the bottom is maintained at about 79°C.
  • the resin is cooled to room temperature and eluted with 6 liters of 2 M NaOH at a rate of 100 ml/min. Analysis of the eluate shows 157 g of the aminocarbinol the recovered aminocarbinol (94 percent recovery based upon the 167 g aminocarbinol held by the resin) having the (R,R):(S,R) enantiomeric ratio of 47:53, respectively.
  • An eighty percent volume fraction of the 2 M NaOH eluate containing the above aminocarbinol is acidified to pH 8.5 with 6 M HCl and extracted with one liter of n-butanol.
  • the aqueous layer is re-extracted twice with 200 ml of n- butanol.
  • the combined n-butanol extracts are agitated with 180 g of dibenzoyltartaric acid (DBTA) at 50°C for 16 hours and at 30°C for 8 hours to form the DBTA salt which crystallizes out of solution.
  • DBTA salt of the RR isomer is isolated by filtration and dried to give 70.6 g having a chemical purity of 97 percent.
  • the cycle is repeated
  • the aminocarbinol loading is 136 g.
  • the stereoisomer ratio after elution by 2 N NaOH is (RR, SR) having an enantiomeric ratio of 48:52.
  • a third cycle is performed.
  • the loaded carbinol is 145 g.
  • the recovered aminocarbinol in the 2 N NaOH (6.7 liters) is 141 g.
  • the title compound of (R,R, S,R) has an enantiomeric ratio of 52:48.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de préparation d'un mélange racémique contenant des quantités approximativement équimolaires de stéréo-isomères de la formule (I), ou leurs sels, dans laquelle R?1, R2, R3, R4, R5 et R6¿ représentent indépendamment hydrogène, alkyle, alkyle substitué, aryle, aryle substitué, hétérocyclique aromatique ou hétérocyclique aromatique substitué, ou une fraction salicylamide, à condition que R1 ne représente pas hydrogène, alkyle ou alkyle substitué, ou leurs sels, dans laquelle R?7, R8 et R9¿ représentent indépendament n'importe laquelle des valeurs de R?1, R2, R3, R4, R5 et R6¿, comprenant les étapes consistant (a) à mettre en contact un composé optiquement actif de la formule (II) ci-décrite, (b) à chauffer la résine contenant les composés de la formule (II) à une température efficace pour produire le mélange racémique de la formule (I); et (c) à récupérer les composés de la formule (I) de la résine.
PCT/US1990/006511 1989-11-17 1990-11-15 Procede de preparation d'arylethanolamines a partir de precurseurs d'aminocarbinol WO1991008196A2 (fr)

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US43882689A 1989-11-17 1989-11-17
US438,826 1995-05-11

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WO1991008196A2 true WO1991008196A2 (fr) 1991-06-13
WO1991008196A3 WO1991008196A3 (fr) 1991-08-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0542098A1 (fr) * 1991-11-15 1993-05-19 Degussa Ag Procédé de racémisation d'hydantoines 5-substituées, dispositif de mise en oeuvre du procédé et utilisation de l'hydantoine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2536360A (en) * 1949-11-25 1951-01-02 Du Pont Racemization of lysine
US4066755A (en) * 1969-07-08 1978-01-03 Allen & Hanburys Limited Phenylaminoethanol derivatives for treating hypertension
US4096186A (en) * 1974-06-29 1978-06-20 Teijin Limited Process for racemizing optically active amino compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2536360A (en) * 1949-11-25 1951-01-02 Du Pont Racemization of lysine
US4066755A (en) * 1969-07-08 1978-01-03 Allen & Hanburys Limited Phenylaminoethanol derivatives for treating hypertension
US4096186A (en) * 1974-06-29 1978-06-20 Teijin Limited Process for racemizing optically active amino compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0542098A1 (fr) * 1991-11-15 1993-05-19 Degussa Ag Procédé de racémisation d'hydantoines 5-substituées, dispositif de mise en oeuvre du procédé et utilisation de l'hydantoine
US5449786A (en) * 1991-11-15 1995-09-12 Degussa Aktiengesellschaft Method for the chemical racemization of 5-monosubstituted hydantoins by contact with anionic ion exchanger

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AU7166991A (en) 1991-06-26
WO1991008196A3 (fr) 1991-08-08

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