EP0248879A4 - Herstellung von aryloxypropanolaminen und aryläthanolaminen. - Google Patents

Herstellung von aryloxypropanolaminen und aryläthanolaminen.

Info

Publication number
EP0248879A4
EP0248879A4 EP19870900373 EP87900373A EP0248879A4 EP 0248879 A4 EP0248879 A4 EP 0248879A4 EP 19870900373 EP19870900373 EP 19870900373 EP 87900373 A EP87900373 A EP 87900373A EP 0248879 A4 EP0248879 A4 EP 0248879A4
Authority
EP
European Patent Office
Prior art keywords
aryl
alkyl
metal
propoxy
chiral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19870900373
Other languages
English (en)
French (fr)
Other versions
EP0248879A1 (de
Inventor
Ghanshyam Patil
Khuong H X Mai
William L Matier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP0248879A1 publication Critical patent/EP0248879A1/de
Publication of EP0248879A4 publication Critical patent/EP0248879A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Aryloxypropanolamines and arylethanolamines are widely used therapeuttc agents, particularly those compounds possessing potent betaadrenergic receptor blocking activity. These beta-adrenergic blocking agents are widely used for a number of cardiovascular therapeutic indications, such as hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction and more recently in the treatment of glaucoma.
  • certain ary loxypropanolamines possess potent beta-adrenergic stimulating properties and such compounds are used as cardiac stimulants.
  • the R isomers are less active or essentially devoid of beta-blocking activity as compared to their counterpart S isomers.
  • the R-isomer beta-agonists are more potent agents than their S-isomer counterparts.
  • p-TsCI p-toluenesufonyI chloride
  • R Ms or Ts
  • R 1 H 4b
  • Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, substituted alkyl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B is -NR 2 COR 3 , -NR 2 CONR 3 R 4 , -NR 2 SO 2 R 3 , -NR 2 SO 2 NR 3 R 4 , or -NR 2 COOR 5 , where R 2 , R 3 , R 4 , and R 5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R 3 and R 5 are not hydrogen when B is -NR 2 SO 2 R 3 or -NR 2 COOR 5 , or R 3 and R 4 may together with N form a 5- to 7-member
  • the method involves the utilization of trisubstituted phosphonlum hal ides such as R 3 P/CCI 4 as selective chlorinating agents to provide the monochloro derivative 5.
  • the chlorohydrin 5 is then converted into the aryloxypropanolamine 2 in the same reaction vessel or in separate steps as desired. It is noted that the undesirable dichloro intermediate 6 is not formed or formed in insignificant amounts in this reaction.
  • the method does not cause racemization of the optically active intermediate or final product and produces high purity chiral products. No complex separation steps are required to isolate a particular isomer. the three consecutive steps in the process may be performed in a single reaction vessel if desired. This makes the process much more efficient. Moreover, the method allows the use of economical starting materials.
  • Ar is aryl, substituted aryl, heteroaryl or aralkyl and R is alkyl, substituted alkyl, aralkyl, or WB wherein W ts a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B represents -NR 2 COR 3 , -NR 2 CONR 3 R 4 , -NR 2 SO 2 R 3 , -NR 2 SO 2 NR 3 R 4 , or -NR 2 COOR 5 wherein R 2 , R 3 , R 4 and R 5 may be the same or different and may be hydrogen, alkyl of from 1 to about 10 carbon atoms and preferably from 1 to about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 10 carbon atoms and preferably fron 1 to about 6 carbon atoms; cycloalkyl of from 3 to about 8 carbon atoms, alkenyl of from 3 to about 10 carbon atoms
  • aryl represents a phenyl or naphthyl group which may be unsubstituted or substituted with alkyl of from 1 to about 6 carbon atoms, alkenyl of from 2 to about 6 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms, halo, acetamido, amino, amido, nitro, alkyIamino of from 1 to about 6 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or aryIalkoxy wherein the alkyl group contains form 1 to about 6 carbon atoms and the aryl group is substituted or unsubstituted phenyl.
  • heteroaryI represents pyridine, pyrazine, pyrrole, pyrazole, piperazine, thiophene, benzothiophene, furan, benzofuran, Imldazole, oxazole, indole, carbazole, thiazole, thiadiazole, benzothiadiazole, triazole, tetrazole, azepine, 1, 2-diazepine, or 1,4-thiazepine.
  • the heteroaryl is selected from the group consisting of pyridine, pyrazine, thiophene, benzothfophene, benzofuran, indole, carbazole, thiadiazole or benzothiadiazole, with the most preferred being pyrazine, indole, 1,2, 5-thiadiazole, or benzofuran.
  • heterocyclic as used herein represents pyrrolidine, piperidine, morphol ine, or thiomorphol ine.
  • the alkyl group contains from about 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstltuted monocyclic or polycyclic aromatic or heterocycl ic ring systems of from 5 to about 10 carbon atoms, such as benzyl, phenethyl, 3,4-dimethoxyphenethyl, 1,1-dimethyl-2-(3-indolyl)-ethyI and the l ike.
  • Aromatic (Ar) substituents may include lower alkyl of from 1 to about 10 carbons atoms, alkenyl of from 2 to about 10 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 10 carbon atoms, halo, acetamido, amino, nitro, alkyIamino of from 1 to about 10 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 10 carbon atoms, cyano, aryIalkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstituted phenyl and groups of the formula
  • R 4 -O-C-A wherein R 4 is lower alkyl, aryl or aralkyl and A is a direct bond, alkylene of from 1 to about 10 carbon atoms or alkenylene of from 2 to about 10 carbon atoms.
  • cycloalkyl refers to cycl ic saturated al iphatic radicals containing 3 to 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyI.
  • the method involves the utilization of trisubstituted phosphonium hal ide, namely the R 3 P/CX 4 complex as selective halogenating agents, an example being the use of Ph 3 P/CCl 4 as selective chlorinating agents to provide the monochloro derivative, which is then converted into the aryloxypropanolamine.
  • the complete process can be performed in one reaction vessel to avoid having to isolate and purify intermediates, or can be performed stepwise.
  • the method can be used in the synthesis of beta agonists or beta-bIockers or any halohydrin intermediate.
  • R represents alkyl, aryl, cycloalkyl, alkylamino, aminoalkyl, cycloalkyl, amino or amino cycloakyl.
  • X represents halo, namely chloro, bromo or iodo.
  • the arylethanolamines can be prepared as follows, all in a single reaction vessel.
  • Aryl 1,2-ethanediol can be converted to the corresponding chlorohydrln by reacting it with Ph 3 P and CCI 4 in acetonitriIe.
  • the resulting chlorohydrin then can be cycl ized to an epoxide by treating it with one equivalent of sodium methoxlde.
  • the aryiethanolamine can then be obtained by treating the epoxide with one equivalent of amine.
  • the racemic, the (R)-(+) or S-(-) 3-(aryloxy)-1,2- propanediol (1) can be made by known methods.
  • the S-enantiomer can be prepared readily by reacting an appropriate phenoxide with R-(-)-2,2-dimethyl-4-(hydroxymethyl)-1,3- dioxolane methanesulfonate or p-toluene-sulfonate, followed by acid hydrolysis of the ketal.
  • the aryloxypropanolamine (4) can be made by mixing in the same reaction vessel, in the following named order, the 3-(aryloxy)-1,2- propanediol (1) with a trisubstituted phosphonium hal ide to prepare the aryl substituted halohydrin (2) which, unless desired, need not be isolated. A suitable base is then added to prepare the epoxide which, likewise, need not be isolated. A selected amine is then added to prepare the desired aryloxypropanolamine.
  • a suitable base for reaction with the halohydrin would be a metal alkoxide, metal hydroxide, metal hydride, metal carbonate or metal bicarbonate wherein the metal is sodium, potassium or calcium, or an ammonium hydroxide or a suitable organic base.
  • Preferred organic bases are pyridine, dlmethylaminopyridine, dimethylaniI ine, quinol ine,
  • DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-Diazabicyclo[4,3.0]non- 5-ene
  • Preferred bases are sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine.
  • beta-adrenergic blocking agents beta-agonists and partial agonists are representative of the compounds that can be made using the described process:
  • the solid was recrystaiIized from methyl ethyl ketone (MEK)/ether (200 mL/35 mL) to give white crystalline product (28.6 g, 29.7%), mp 91-94° C, -19.1 (C 1, MeOH).
  • MEK methyl ethyl ketone
  • the resulting mixture was diluted with 100 mL ethanol and treated with isopropylamine (10 mL, 2.4 equiv.) and refluxed for 2 hours.
  • the reaction mixture was evaporated to dryness.
  • the oily residue was taken up with ether (200 mL) and washed with water (2 x 200 mL) and then extracted with 1N hydrochloric acid (1 x 500 mL).
  • the ethereal layers were combined and acidified with hydrogen chloride until a pH of 2 was obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Indole Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
EP19870900373 1985-12-04 1986-11-14 Herstellung von aryloxypropanolaminen und aryläthanolaminen. Withdrawn EP0248879A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80440685A 1985-12-04 1985-12-04
US804406 1985-12-04

Publications (2)

Publication Number Publication Date
EP0248879A1 EP0248879A1 (de) 1987-12-16
EP0248879A4 true EP0248879A4 (de) 1990-02-26

Family

ID=25188898

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870900373 Withdrawn EP0248879A4 (de) 1985-12-04 1986-11-14 Herstellung von aryloxypropanolaminen und aryläthanolaminen.

Country Status (6)

Country Link
EP (1) EP0248879A4 (de)
JP (1) JPS63502585A (de)
AU (2) AU604005B2 (de)
CA (1) CA1282787C (de)
WO (1) WO1987003583A1 (de)
ZA (1) ZA868713B (de)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4990668A (en) * 1985-12-04 1991-02-05 E. I. Du Pont De Nemours And Company Optically active aryloxypropanolamines and arylethanolamines
SE8801518D0 (sv) * 1988-04-22 1988-04-22 Astra Pharma Prod A novel process
US5032584A (en) * 1988-10-26 1991-07-16 G. D. Searle & Co. S-diastereomer of an n6 -((2-hydroxypropyl)aryl)adenosine and its medicinal uses
US5030624A (en) * 1988-10-26 1991-07-09 G. D. Searle & Co. R-diastereomer of an N6 -[(2-hydroxypropyl)aryl]adenosine and its medicinal uses
US4992535A (en) * 1988-10-26 1991-02-12 G. D. Searle & Co. Methods of making novel R and S diastereomers of N6 -[(2-hydroxypropyl)aryl]adenosines
DE3844410A1 (de) * 1988-12-30 1990-07-19 Lindner Wolfgang Inversion der alkohol-konfiguration in alpha-aminoalkoholen ueber intramolekulare substitution der sulfonsaeureester
US5629345A (en) * 1993-07-23 1997-05-13 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
US5965620A (en) * 1993-07-23 1999-10-12 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
AR011626A1 (es) * 1997-02-07 2000-08-30 Shell Int Research Un procedimiento para la elaboracion de compuestos epoxidos, resinas epoxidas obtenidas mediante dicho procedimiento y un procedimiento para laelaboracion de compuestos intermedios para la elaboracion de compuestos epoxidos
AU2012211309B2 (en) * 2011-01-27 2014-10-09 Baxter Healthcare Sa Use of (S) - esmolol for controlling venous irritation associated with the treatment of a cardiac disorder
US8686036B2 (en) * 2011-01-27 2014-04-01 Baxter International Inc. Methods of controlling heart rate while minimizing and/or controlling hypotension
CN102408285B (zh) * 2011-09-15 2013-11-20 东北师范大学 一种甲苯衍生物的苄基碳氢直接胺化方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4202978A (en) * 1978-02-08 1980-05-13 Hoffmann-La Roche Inc. (S)-1-[2-(4-(2-Hydroxy-s-(1-alkylaminopropoxy)phenylalkyl]-4-phenylpiperazines
US4990668A (en) * 1985-12-04 1991-02-05 E. I. Du Pont De Nemours And Company Optically active aryloxypropanolamines and arylethanolamines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., vol. 46, 1981, pages 3361-3364, American Chemical Society; C.N. BARRY et al.: "Triphenylphosphine-tetrachloromethane promoted chlorination and cyclodehydration of simple diols" *
See also references of WO8703583A1 *
TETRAHEDRON LETTERS, vol. 24, no. 7, pages 661-664, Pergamon Press Ltd, GB; C.N. BARRY et al.: "Chlorination and cyclodehydration of 1,2-diols with the "triphenylphosphine-tetrachloromethane-potassium carbonate" reagent" *

Also Published As

Publication number Publication date
CA1282787C (en) 1991-04-09
ZA868713B (en) 1987-06-24
AU6774987A (en) 1987-06-30
JPS63502585A (ja) 1988-09-29
AU5756290A (en) 1990-10-11
AU631433B2 (en) 1992-11-26
WO1987003583A1 (en) 1987-06-18
EP0248879A1 (de) 1987-12-16
AU604005B2 (en) 1990-12-06

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Inventor name: MATIER, WILLIAM, L.

Inventor name: PATIL, GHANSHYAM

Inventor name: MAI, KHUONG, H., X.