AU604005B2 - Synthesis of aryloxypropanolamines and arylethanolamines - Google Patents
Synthesis of aryloxypropanolamines and arylethanolamines Download PDFInfo
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- AU604005B2 AU604005B2 AU67749/87A AU6774987A AU604005B2 AU 604005 B2 AU604005 B2 AU 604005B2 AU 67749/87 A AU67749/87 A AU 67749/87A AU 6774987 A AU6774987 A AU 6774987A AU 604005 B2 AU604005 B2 AU 604005B2
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- 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
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
2 iy T WRLDO ELLECTUAL PROPERTY ORGANIZATION IQ International Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4: (11) International Publication Number: WO 87/ 03583 C07C 57/00, 67/02, 93/06 C07D 209/82, 215/36, 237/02 Al C07D 239/02, 261/06, 265/30 (43) International Publication Date: 18 June 1987 (18.06.87) C07D 277/04 (21) International Application Number: PCT/US86/02406 (74) Agent: FATO, Gildo, Du Pont Critical Care, Subsidiary of E.I. Du Pont de Nemours Co., 1600 (22) International Filing Date: 14 November 1986 (14.11.86) Waukegan Road, Waukegan, IL 60085 (US).
(31) Priority Application Number: 804,406 (81) Designated States: AU, CH (European patent), DE (European patent), FR (European patent), GB (Euro- (32) Priority Date: 4 December 1985 (04.12.85) pean patent), IT (European patent), JP, SE (European patent).
(33) Priority Country: US Published (71) Applicant: E.I. DU PONT DE NEMOURS CO., With international search report.
(INC.) [US/US]; 1007 Market Street, Wilmington, DE 19898 W 23 JUL 1987 (72) Inventors: PATIL, Ghanshyam 340 Albert Drive, Ver- US RAnon Hills, IL 60061 MAI, Khuong, X. 108 South Orchard, Waukegan, IL 60085 MATIER, William, L. 1214 Parliament Court, Libertyville, IL 30 JUN 9 60048 (US).
This document contains the
C~
amendments made under Section 49 and is correct for r 6 7 4 9 8 7 ,W 6774 9 87 prinng S(54) Title: SYNTHESIS OF ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES Ar-O
NHR
OH
1
OH
Ar ,NHR 2 (57) Abstract A process for preparing a racemic or chiral aryloxypropanolamine or arylethanolamine of the formula or wherein 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 -NRzCOR 3
-NR
2
CONR
3
R
4 NRSO2R3, -NR 2
SO
2
NR
3
R
4 or -NRiCOOR 5 where R 3
R
4 and R 5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynil, aryl, heteroaryl, or aralkyl, except that R 3 and R 5 are not hydrogen when B is -NR.SO 2
R
3 or -NR 2 COORs, or R 3 and R 4 may together with N form a 5- to 7-membered heterocyclic group. The process can be used to prepare beta-blocking agents, useful in the treatment of cardiac conditions.
I: L-, WO 87/03583 PCT/US86/02406 -1- SYNTHESIS OF ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES BACKGROUND OF THE INVENTION Aryloxypropanolamines and arylethanolamines are widely used therapeutic 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 pectorls, cardiac arrhythmias, myocardlal Infarction and more recently In the treatment of glaucoma. In addition, certain aryloxypropanolamines possess potent beta-adrenergic stimulating properties and such compounds are used as cardiac stimulants.
Among beta-blocker oxypropanolamines, the R Isomers are less active or essentially devoid of beta-blocking activity as compared to their counterpart S Isomers. Similarly, the R-lsomer beta-agonists are more potent agents than their S-Isomer counterparts.
H OH HO, H Ar-0 O NHR Ar-0
NHR
Conventional methods for preparing such compounds utilize the nonselective mesylation or tosylation of the diol 3 followed by the separation of monomesylate or monotosylate 4a from the undesirable dimesylate or dltosylate 4b. Subsequently, the monomesylate or tosylate is transformed Into an epoxide which is then treated with the corresponding amine to provide the desired beta-blocker In separate stages. Such a procedure Is described by Tsuda et al. in CHEM. PHARM. BULL. 29 (12) 3593-3600 (1981). In such a procedure, to prepare monotosylate, p-toluenesufonyl chloride (p-TsCI) is used, which is not a very selective reagent and significant quantitles of undesirable ditosylate are also formed. This considerably reduces the yield of the desired monotosylate and, generally, extensive purification of the mixture is required In order NVO, 87/03583 WO 8703583PCT/US86/02406 to obtain the monotosylate. Frequently this Is not possible In a large.
scale manufacturing process and this process is uneconomnical as a means to obtain isomners. An efficient and an economiical process for preparing the separate Isomers Is therefore highly desirable.
HO H R 1 0O H 3 4 4a, R-Ms or Ts, R 1
=H
4b, R-=R 1 Ms or Ts SUMMARY OF THE INVENTION In accordance with the present Invention, disclosed Is aLrpFece s for preparing a racemic or chiral aryloxypropanoiamine cr arylethanolamine of the formula Ar -0 NHR or O1
OH
A r NHR wherein 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 iNR 3
R
4 or -NRI 2
COOR
5 where R 2
R
3
R
4 and R 5 may be the same or different and may be hydrogen, alkyl, alko alkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl aralkyl, except that R 3 and R 5 are not hydrogen when B Is 2 S0 2
R
3 or
-NR
2 000R 5 or R 3 and R 4 may together with N formr to 7-membered heterocycliIc group.
As an example, the od Involves the utilization of trisubstituted phosphonium hal s such as R 3 P/C01 4 as selective chlorinating agents to provid e monochloro derivative 3 R4, and R 5 may be the same or different and are selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and aralkyl, except that R 3 and R are not hydrogen when B is -NR 2
SO
2
R
3 or
-NR
2
COOR
5 or R 3 and R 4 together with N form a to 7-membered heterocyclic group.
As an example, the method involves the utilization of trisubstituted phosphonium halides such as R3P/CCI 4 as selective chlorinating agents to provide the monochloro derivative HO H Cl H Ar-O Cl Ar-O Cl 6 The chlorohydrin 5 is then converted into the aryloxypropanolamine 1 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 20 method does not cause racemization of the optically active intermediate or final product and produces high purity S" 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 25 vessel if desired. This ma<es the process much more efficient. Moreover, the method allows the use of economical starting materials.
4 DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, disclosed is a method of preparing a racemic or chiral aryloxypropanolamine or chiral arylethanolamine of the formula
OH
Ar-O 'NHR or Ar- /NHR
OH
1 2 wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, aryl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to 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 are selected from the group consisting of hydrogen, C -C 10 alkyl, preferably
C
1
-C
6 alkyl, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, C 3
-C
6 cycloalkyl, C 3
-C
10 alkenyl, alkoxyaryl wherein the alkyl group contains from 1 to 6 carbon atoius, C 3
-C
10 alkynyl, aryl as herein defined, heteroaryl as herein defined and aralkyl as herein defined, except that R 3 and R 5 are not hydrogen when B is -NR 2
SO
2
R
3 or °ri 25 -NR 2
COOR
5 or R 3 and R 4 together with N form a to 7-membered heterocyclic group, which method comprises: 4a mixing, in the named order, in a single reaction vessel, a selected racemic or chiral 3-(aryloxy)-1,2-propanediol or chiral aryl 1,2-ethanediol of the formula
OH
Ar-O r OH or Ar OH
OH
wherein Ar is as defined above, and a trisubstituted phosphonium halide to prepare an aryl substituted halohydrin of the formula
OH
Ar-O /X or Ar-X
OH
wherein Ar is as defined above and X represents chloro, bromo or iodo, and a suitable base, to prepare an epoxide of the formula Ar-0 0 or Ar 0 wherein Ar is as defined above and a selected amine RNH 2 wherein R is as defined for formula 1 and 2, to thereby prepare the desired aryloxypropanolamine or aryl ethanolamine.
In the definition of R 2
R
3
R
4 and R alkoxyaryl represents groups wherein the alkyl group contains from 1 to 6 carbon atoms.
As used herein, the term "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 4b contains from 1 to about 6 carbon atoms, halo, acetamido, amino, amido, nitro, alkylamino of from 1 to about 6 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or arylalkoxy wherein the alkyl group contains form 1 to about 6 carbon atoms and the aryl group is substituted or unsubstituted phenyl.
The term "heteroaryl" as used herein represents pyridine, pyrazine, pyrrole, pyrazole, piperazine, thiophene, benzothiophene, furan, benzofuran, imidazole, oxazole, indole, carbazole, thiazole, thiadiazole, benzothiadiazole, triazole, tetrazole, azepine, 1,2-diazepine, or 1,4-thiazepine. Perferably, the heteroaryl is selected from the group consisting of Spyridine, pyrazine, thiophene, benzothiophene, benzofuran,
Q
c 15 indole, carbazole, thiadiazole or benzothiadiazole, with °a the most preferred being pyrazine, indole, 0o 1,2,5,-thiadiazole, or benzofuran.
o o Sv o o o 0 o WO 87/03583 PCT/US86/02406 The term "heterocyci c" as used herein represents pyrrolIdlne, piperldine, morphollne, or thlomorpholine.
In the term "aralkyl" as used herein, the alkyl group contains from about 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstituted monocyclIc or polycyclic aromatic or heterocyclic ring systems of from 5 to about 10 carbon atoms, such as benzyl, phenethyl, 3,4-dlmethoxyphenethyl, 1,1-dimethyl-2-(3-indolyl)-ethyl and the I ke.
Armaatic (Ar) substituents may Include lower alkyl of from 1 to about carbons atans, 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, acetamldo, amino, nitro, alkylamino of from 1 to about 10 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about carbon atoms, cyano, arylalkoxy wherein the alkyl group contains frmn 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstituted phenyl and groups of the formula 0
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 carbon atoms.
The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic radicals containing 3 to 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The method Irvolves the utilization of trisubstituted phosphonium hal Ide, Inamalythe R 3
P/CX
4 complex as selective halogenating agents, an example being the use of Ph 3
P/CCI
4 as selective ch.lorlnating 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 agonlsts or beta-blockers or any halohydrin Intermediate. In the WO 87/03583 WO 8703583PCT/US86/02406 R3-phosphines, as used herein R represents alkyl, aryl, cycloalkyl, alkylamino, aminoalkyl, cycloalkyl, amino or amino cycloakyl. X represents halo, namely chioro, brcxno 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 chlorohydrin by reacting It with Ph 3 P and CC1 4 In acetonitrile. The resulting chlorohydrin then can be cyci ized to an epoxide by treating It with one GquIvalent of sodium methoxide. The arylethanol amine can then be obtained by treating the epoxide with one equivalent of amine.
The following reaction schem~es summarize the process of the present invention.
SCHEME 1
HOI"
MsC1 CH 3 so 2
Q
ArONa ArO l" R- or or or AcOH* oArO >7
R
3 P/CC1 4 Aro-- 2 OH C1 or orR- RO-Na ArO RNH 1 ArO
HR
4 OH or o or WO 87/03583 WO 8703583P CT/US86/02406 SCHEME 2
OH
0 OH 0 Ph 3 P/CC1 4
/CH
3
CN
CO2 CH3
OH
Q NaOCH 3 /CH 3
OH
2 CO 2 CH 3 0 0- co 2 CH 3 H 2 1 O H 0 N* 0 *HC1 co 2 CH 3 0 SCHEME 3 0 CH CH 0 C OH N s/N
CH
3 NaH/DMAC 0 3 CH 3 0 2 so CHI CH 0 32 2 N\ N
S
H
3 3 0 0 80% aq.CH 3
CO
2
H
0 OH CH CH
U
2
OH\
N \/N
S
Ph 3 P/C 14
OH
CH CH 2 C 0I NaOEt/EtOH 2
OH
NHj- CH CH 2 C N \/N s -0 CH 3 CH 2 O0 2 II H 2 N E tOll WO 87/03583 PCT/US86/02406 -9- Referring to Scheme 1, the racemic, the or 3-(aryloxy)-1,2- propanediol(1) can be made by known methods. For example, the S-enantlcmer can be prepared readily by reacting an appropriate phenoxide with R-(-)-2,2-dlmethyl-4-(hydroxymethyl)-1, 3 dioxolane methanesul fonate or p-toluene-sul fonate, followed by acid hydrolysis of the ketal.
The aryloxypropanolamine can be made by mixing in the same reaction vessel, In the following named order, the 3-(aryloxy)-1,2propanedlol with a trisubstituted phosphonlum halide to prepare the aryl substituted halohydrin 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 pyrldine, dimethylamlnopyrldine, dimethylanillne, quinoline, 1,8-DiazabicycloC5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4,3.0]non- (DBN) or tertiary alkylamines. Preferred bases are sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine.
The following beta-adrenergic blocking agents, beta-agonlsts and partial agonlsts are representative of the compounds that can be made using the described process:
J
WO 87/03583 PCT/1iS86/02406 10-
OH
wAr-O NH-R Ar-O H
OH
Ar R Comoound I COCu LIM 3
CH
3 002
-F
Acebutolol Adimolol
-F-
Af urol ol 0 CH 2 CH=CH 2
-K
Al prenal al Ancaral al Atenal al
-K
0 COCH 3 CH CH O-CH-< Befunal al
-K
Betaxol ol 7 WO 87/03583 Ar PCT/US86/02406 -11- Compound Bevantol ol
OCH
3 CH 2 CH 2 OCH 3 0 CH 2-O-CH O H Bi sprol ol
-K
CH 2 CH 2 Q OCH 3 0 CH 3 Bometolol 0, Bornaprol al -Ij C N
N
H
Buci ndol al Bucumol al Bufetol al 0 WO 87/03583 WO 8703583PCT/1JS86/02406 -12- Ar aCN Compound
-F-
A-
-F
Buni trol ol Bunal ol Bupranol ol Butocrol ol Butofilolol Carazol ol Carteolol
-K
-F
CH 2 CH 2 0 CH 3 0 Carvedilol WO 87/03583 Ar R CO CH 1 3 PCT/L'S86/02406 Compound Cel i prol ol OCH 2 CONHCH 3 Cetamolol
CH
2 0H 2 CH 2 Q Chinoin-103 Cidoprolol C1 oranol ol COCH 3 CH 3
COHN
-H
Diacetol ol Exaprol ol WVO 87/03583 -4 IAr R
N-O-
PCT/US86/02406 Compound IPS-339 I ndenol a] I ndopanao al 0
-K
0 C =C I saxapral al Levobunol ol Mepi ndal al Metipranal a] CH 0
C
3
N
CH COOCH 3
-K
-K
CH
3 I WO 87/03583 WO 8703583PCT/US86/02406 Compound CH 3 OCH 2 CH Q D OCH 3 0
-K
-F
Metoprol ol Moprol al Nadolol Nafetol al
HO
H w
HO
0 OCH 3 OCH 3 0~ Oxprenol al Pacri nol al 0
NHCONH-K
0 NHCOOCH 3 Pafenol al Pamatol al
-K
ba.-I WO 87/03583 Ar PCT/LiS86/02406 -16- Compound Pargolol Penbutolol Pindolol N6
H
-K
-H 3
LI
Pirepolol CH 3
CONH
2 0 0
OH
-K
-K
Practol al Prenal terol Prizidilol Proci nol al 0
-K
7 WO 87/03583 PCT/US86/02406 Compound 00
-K
Propranol ci CH CH0 2 2\ 11 CH 3 N
N
Spirendol ci Teoprol ci 0 0 SCH 3
CH
3 ~CH3 0
OH
Tertatol ci Timol ol
-K
Tiprenolol CONH 2 0 N H'N Tel ama] ci Xibenol ci Xamoterol WO 87/03583 WO 8703583PCT/US86/02406 -18-
OH
NH -R Ar R Compound
OH
K> OH Al buterol H 3 H 2NO0 2 0- CH 2 CH 2 OCH 3 Amosul al ol Et QO Bufuralol 0 CH 2 so 2 CH 3
OH
Sul fonterol Ibuterol 2 WNO 87/03583 PCT/US86/02406 -19- Miscellaneous Beta-Blockers Compound S H~ SO -CONH 2 Arotinolol 0 Bopindol ol WO 87/03583 PCT/US86/02406 In order to illustrate the manner In which the above compounds may be made, reference Is made to the following examples, which, however, are not meant to limit or restrict the scope of the invention in any respect.
EXAMPLE 1 Preparation of Methyl 3-F4-FF2-hydroxy-3sopropylamine)propoxylphenyl1propionate Hydrochlorlde OH
OH
0 OH 0 NH Ph 3 P/CC1 4
/CH
3 CN HC1 NaOCH 3
/CH
3 0H
H
2 CO2CH CO 2CH 3
MEK/HCL
A mixture of (S)-(-)Methyl 3-C4-(2,3-dihydroxypropoxy)phenyl proplonate (74 g, 0.29 mole), triphenylphosphine (85 g, 1.1 mole) and carbon tetrachlorlde (140 mL) in 400 mL acetonitrlle was stirred at 22* C for 16 hours. Another 8.5 g of triphenylphosphine was added and stirring was continued for another 3 hours. If desired, the product 2 can be isolated at this stage. The clear solution was cooled In an ice- Isopropanol bath and to this was added dropwise 62.8 gms. of 25% sodium methoxide solution in methanol over 30 minutes. The Ice bath was removed and the solution was stirred at 22* C for 20 hours. To this solution was added 50 mL of Isopropylamine and the mixture was refluxed for 4 hours.
The reaction mixture was evaporated to dryness. The solidified mixture was liqulfied, treated with 1000 mL ether, and filtered over celite. The filtrate was treated with hydrogen chloride for 5 minutes (pH 2) and Immediately the oil began to separate. This oil was isolated by decanting the ethereal layer. This process was repeated three times using 250 nm ether and the oil was solidlfied. The sol d was recrystallized from methyl 7 WO 87/03583 PCT/US86/02406 -21ethyl ketone (MEK)/ether (200 mL/35 mL) to give white crystalline product (28.6 g, mp 91-94° C, a 2 5 -19.1 (C 1, MeOH).
D
Anal. Cal. for C 1 6
H
2 6 CIN0 4 Cal: Found: C, 57.91; H, 7.90; N, 4.22 C, 57.98; H, 7.91; N. 4.13 EXAMPLE 2 Preparation of S-(+)-Methyl 3-i4-(2.3-epoxypropoxy)phenyllpropionate
OH
0 ,OH
CO
2
CH
3 Ph 3 P/CC1 4
/CH
3
CN
K
2
CO
3 0 0 CO 2 CH 3 A mixture of S-(-)-Methyl 3-C4-2,3-dIhydroxypropoxy)phenyl]propIonate (50.8 g, 0.2 mole), triphenylphosphine (58 g, 0.22 mole), and carbon tetrachloride (100 g, 0.65 mole) in 500 mL acetonltrile was stirred at 22° C for 24 hours. To the solution was added anhydrous potassium carbonate g, 0.3 mole) and the mixture was refluxed with stirring for 48 hours.
The mixture was evaporated to dryness to give an oil, which was sol Idlfled Immediately. To this was added 600 mL hexane and the mixture was refluxed with vigorous stirring for 10 minutes and decanted while It was hot. This procedure was repeated four times. The decanted solution was cooled to 22° C and triphenylphosphine oxide was filtered off. The hexane solution was evaporated to give an oil (29 g) which was distilled under reduced pressure to give 22.5 g of the titled compound as a clear oil, b.p.
1500 (0.1 mm Hg), a 25 +7.9 (C 0.66, MeOH).
D
WO 87/03583 WO 8703583PCT/US86/02406 -22- EXAMPLE 3 Preparation of (S)-(-)-Methyl 3-F4-2-hydroxy-3- 1fsopropyl amine)propoxylphenyl~proplonate LHydrQb ;r.loda
OH
0 N NH< -HC1 H 2 /CH 3
OH
MEK/HG1 A solution of (S)-(+)-Metiyi 3-[4-(2,3-epoxy propoxy) ph enylI]prop Ionate (22 g, 92.7 rmole) and isopropylamine (50 ml-) In 50 rrL methanol was ref luxed for 2 hours and evaporated to dryness. The oily residue was redissolved in 100 ml- methanol and the solution was evaporated. This procedure was repeated twice to el iminate traces of isopropylanine. The clear oil was dissolved In 200 rri methyl ethyl ketone, acified with hydrogen chloride, treated with 100 ni. ether, seeded and allowed to stand at 220 C fcor 16 hours. The white crystal line sol id was filtered, washed with ether followed by hexane and air dried to yield 21.6 g of the titled product, mp 91-95* C, a25 -19.3 (C 1, MeOH).
0 Anal. for C 16
H
26
CINO
4 Cal: Found: C, 57.91; H, 7.90; No 4.22 C, 57.99; H, 7.79; N, 4.14 'WO 87/03583 PCT/US86/02406 -23- EXAMPLE 4 Preparation of evo-Proprano'L, Hl~QLor (S)-(-)F(3-IsoproynvlamIno-2chIoro)propoxylnaptha ene Hydrochloride OH Ph 3 P/CC 4/CH 3 CN OH 0 OH NaOCH 3 /CH3OH 0 NH-- 0
H
2
HC
HC1 A solution of (S)-(-)-1-(2,3-dlhydroxypropoxy)-napthalene (10.9 g, 0.05 mole), triphenylphosphlne (14.4 g, 0.055 mole) and carbon tetrachlorlde (10.5 mL, 2.2 equiv.) In dry acetonitrile (dried over 3A Mol-sieve) was stirred at 220 C. Within 5 minutes this mixture became a clear, homogenous solution. Stirring was continued for 20 hours at 220 C and the mixture was then placed in an Ice bath. To this was added 11.4 mL of 25% solution of sodium methoxide In methanol and the ice bath was removed and stirring continued for 16 hours at 22* C. The resulting mixture was diluted with 100 mL ethanol and treated with isopropylamtne 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 IN hydrochloric acid (1 x 500 rL). The aqueous layer was washed with ether (1 x 200 mLi), baslfled with 2N sodium hydroxide (pH 10) and extracted with ether (2 x 200 mL). The ethereal layers were combined and acidified with hydrogen chloride until a pH of 2 was obtained. The precipitated crystalline mass was filtered, washed with ether and air dried to give 14.1 g of crude levo-propranolol. The crude product was recrystall zed from isopropanol (200 mL) to give 6.62 g of crystalline product, mp 190-191° C (Lit. 189-1900 a 25 -26.5 (C1, EtOH) (Lit: a 25 -25.5 0 D (Cl, EtOH)).
WO 87/03583 WO87/ 3583PCT/US86/02406 -24- The mother liquor was treated with 200 n-L elther to give 1.62 g mp 189-190* C) of more crystal line I evo-propranol 01. The above products were combined to give 55.9% yield fromn the diol.
NW~ data: Anal'. for C1 6
H
2 oNO2VHCI Cal: C, 65.17; H, 7.18; N, 4.75 Found: C, 64.87; H, 7.21; N, 4.81 EXAMPLE Preparation of (R)-F(3-Chiloro-2-hy(droxy)propoxytnapthalene 10 0 OH 00 0
N
i-Pr i-Pr 1 CCl 4 /CH 3
CN
OH
0 Cl A solution of (S)-(-)-1-(2,3-dihydroxypropoxy)-naphthalene (5.45 g., 0.025 mole), 4-(dilsopropylaiiincrnethyl)triphenylphosphine (10 g, 0.0226 mole), carbon tetrachloride (5 ml-) In acetonitrile (100 ml-) was stirred at 220 C for 18 hours. This clear yellow solution was passed thr-ough a dry silica gel pad (1.5 cm x 2 cm, 30 g) and eluted with acetonitrile (50 rrL).
The eluent was evaporated to give a yelo oil. This was treated with Ispropyl elter (50 rl-) and stirred for 15 minutes. The top layer was decanted and evaporated under reduced pressure to give the titled chlorohydrin as a clear cii (4.66 g, 78.8%).
-7 WVO 87/03583 PCT/US86/02.106 EXAMFLE 6 Preparation of (R)-Ethyl 3-FF(3-Chloro-2-hydroxy)propoxyI 1,2.5thf~d rAzoI-4-vI1nrononate
OH
N, N 0 O p
N
i-Pr i-Pr CCI 4 /CH 3CN
OH
N /N
S
A solution of ethyl 3-C3-(2,3-drhydroxy-propoxy) 1,2,5thiadiazol-4-yllpropionate (6.51 g, 0.025 mote), 4-(diisopropylamincmiethy)triphenylphosphine (10g, 0.0266 mole), carbon tetrachloride n'L) and acetonitrile (100 rrL) was stirred at 220 C for 18 hours. This clear solution was passed through a dry sil Ica-gel pad (1.5 cm x 2 cm, g) and eluted with acetonitrile (50 rri). The eluent was evaporated to give a yellow oil. This was then treated wrth Isopropyl ether (50 rrL) and the top layer was separated and evaporated under reduced pressure to give the titled product as a clear oil (5.56 Rf 0.38 (SiC 2 EtOAC:Hexane, a single hanogeneous spot.
WO 87/03583 -26- EXAMPLE 7 PCT/US86/02406 Preparation of 3-F3-(2.3-epoxypropoxy)-1.2.5-thladlazol- 4-yllproplonate
OH
EtO 2C-. -0
OH
S N Ph N N
S
K
2 3 P/CC14
CO
3
/MEK
Et02Clsl_ 0/O 0 N N
S
A mixture of 3-[(2,3-dIhydroxypropoxy)-1,2,5thiadiazol-4-yl] proplonate (6.7g, 24,2 mrole), triphenylphosphlne (8.26 g, 1.3 equv.) and carbon tetrachlorlde (60 mL) was heated under reflux for 16 hours, and evaporated to dryness. The residue was mixed with methyl ethyl ketone (60 mL) and anhydrous potassium carbonate (7.0 This mixture was heated under reflux with vigorous stirring for 36 hours, cooled to 220 C and filtered. The filtrate was evaporated under reduced pressure and the residue was stirred vigorously in hexane (200 mL) for 15 minutes and the hexane layer was then decanted. This process was repeated twice; the organic layers were combined and evaporated under reduced pressure. The crude oil was distilled in vacuo to yield 1.9 g of the titled esterepoxide, b.p. 118-122* C (0.2 mm Hg), a 2 5 +25.3 (C 1.5, EtOH), Rf 0.45 2 1% MeOH In CH2C1 2
Claims (3)
1. A method of preparing a racemic or chiral aryloxypropanolamine or chiral arylethanolamine of the formula OH OH 1 2 wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, aryl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to 6 carbon atoms and wherein B is -NR 2 COR 3 -NR2CONR R -NR2SO2R3, -NR2SO2NR3R 4 or -NR2COOR5, where R 2 R 3 R 4 and R 5 may be the same or different and are selected from the group consisting of hydrogen, C 1 -C 10 alkyl, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to 10 carbon atoms, C 3 -C 6 cycloalkyl, C 3 -C 10 alkenyl, alkoxyaryl wherein the alkyl group contains 1 to 6 carbon atoms, C 3 -C 10 alkynyl, aryl as hereinbefore defined, heteroaryl as hereinbefore defined and aralkyl as hereinbefore defined, except that R 3 and R 5 are not hydrogen when B is -NR 2 SO 2 R 3 or or R 3 and R 4 together with N form a to 7-membered heterocyclic group, which method comprises: mixing, in the named order, in a single reaction vessel, a selected racemic or chiral 3-(aryloxy)-l,2-propanediol or chiral aryl 1,2-ethanediol of the formula Ar-0 OH or Ar OH OH -28- wherein Ar is as defined above, and a trisubstituted phosphonium halide to prepare an aryl substituted halohydrin of the formula Ar-O X or Ar X OH wherein Ar is as defined above and X represents chloro, bromo or iodo, and a suitable base, to prepare an epoxide of the formula Ar-O O or Ar 0 wherein Ar is as defined above and a selected amine RNH 2 wherein R is as defined for formula 1 and 2, to thereby prepare the desired aryloxypropanolamine or aryl ethanolamine.
2. The method of Claim 1 wherein the trisubstituted phosphonium halide comprises an R 3 P/CX 4 complex wherein R represents alkyl, aryl, cycloalkyl, alkylamino, aminoalkyl, cycloalkyl amino or amino cycloalkyl and X represents chloro, bromo or iodo. DATED this31st day of August 1990 E.I. DU PONT DE NEMOURS CO. (INC.) Patent Attorneys for the Applicant: F.B. RICE CO. INTERNATIONAL SEARCH REPORT International Application No P CT US 8 6/0 2 4 0 6 I. CLASSIFICATION OF SUBJECT MATTER (It several classification symbols apply, Indicate all) I According to international Patent Classification (IPC) or to both National Classification and IPC IPC(4): C07C 57/00, C07C 67/02, C07C93/06; See Attachment U.S. 544/168. 544/224. 544/256. 544/312: See Attachment II. FIELDS SEARCHED Minimum Documentation Searched 4 Classification System Classification Symbols 544/168, 544/224, 544/256, 544/312, 546/158, 548/186, U.S. 548/247, 548/303, 548/444, 548/516, 549/289, 549/310, 1549/384, 549/467, 549,471, 549/491: See Attachment Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched 6 III. DOCUMENTS CONSIDERED TO BE RELEVANT 14 Category Citation of Document, 18 with Indication, where appropriate, of the relevant passages 1 Relevant to Claim No. Is X US,A, 4,202,978 (FAHRENHOLTZ ET AL) 1-12 13 May 1980 See col. 7-8,
11-12, 18-20, 23, 33-34 and 39. X N, Agric. Biol. Cnem., 1-12 issued May 1982, Shinobu Iriuchijima et al., Asymmetric Hydrolysis of (+)-1,2-Diacetoxy-3-Chloro- propane and Its Related Compounds with Lipase. Synthesis of Optically Pure(S)-Propranolol, Vol. 46, NO. 5, pages 1153-1157. See pages 1153-54 and 1156. Special categories of cited documents: Is later document published after the international filing date Sdocumnt defining the general state o the art which is not or priority date and not in conflict with the application but document defining the general state of the art which i not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but In the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search 2 Date of Mailing of this International Search Report 1 24 February 1987 0 2 MAR 1987 International Searching Authority t Signature of Auth led Officer ISA/US Hines Form PCT/ISA/210 (second sheet) (October 1981) International Application No. PCT/US86/02406 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET X N, Fieser et al., Reagents for 1-12 Organic Synthesis, Issued 1969, 1974, A Wiley-Interscience Publication, Vol. 2, page 445 and Vol. 4, pages 551-552, Respectively OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1o This international search report has not been established In respect of certain claims under Article 17(2) for the following reasons: 1. Claim because they relate to subject matter tI not required to be searched by this Authority, namely: Claim because they relate to parts of the International application that do not comply with the prescribed require- ments to such an extent that no meanlngful international sparch can be carried out 13 specifically: VIQ OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 1" This International Searching Authority found multiple inventions In this International application as follows: Group I. Claims 1-2 and 7, drawn to amines, classified in Class 564. Group II. Claims 3-6, drawn to esters, classified in Class 560 1.F] As all required additional search fees were timely paid by the applicant, this International search report covers all searchable claims of the international application. 2.j] As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims of the International application for which fees were paid, specifically claims: No required additional search fees were timely paid by the applicant. Consequently, this International search report Is restricted to the Invention first mentioned In the claims: it Is covered by claim numbers: 4.A As all searchableclaims could be searched without effort justifying an additional fee, the International Searching Authority did not invite payment of any additional fee. Remark on Protest I] The additional search fees were accompanied by applicant's proteet E No protest accompanied the payment of additional search fees. Form PCT/ISA/211 (supplemental sheet (October 1981)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80440685A | 1985-12-04 | 1985-12-04 | |
| US804406 | 1985-12-04 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU57562/90A Division AU631433B2 (en) | 1985-12-04 | 1990-06-18 | Synthesis of aryl substituted halohydrins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6774987A AU6774987A (en) | 1987-06-30 |
| AU604005B2 true AU604005B2 (en) | 1990-12-06 |
Family
ID=25188898
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU67749/87A Ceased AU604005B2 (en) | 1985-12-04 | 1986-11-14 | Synthesis of aryloxypropanolamines and arylethanolamines |
| AU57562/90A Ceased AU631433B2 (en) | 1985-12-04 | 1990-06-18 | Synthesis of aryl substituted halohydrins |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU57562/90A Ceased AU631433B2 (en) | 1985-12-04 | 1990-06-18 | Synthesis of aryl substituted halohydrins |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0248879A4 (en) |
| JP (1) | JPS63502585A (en) |
| AU (2) | AU604005B2 (en) |
| CA (1) | CA1282787C (en) |
| WO (1) | WO1987003583A1 (en) |
| ZA (1) | ZA868713B (en) |
Families Citing this family (12)
| 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 (en) * | 1988-04-22 | 1988-04-22 | Astra Pharma Prod | A NOVEL PROCESS |
| 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 |
| 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 |
| DE3844410A1 (en) * | 1988-12-30 | 1990-07-19 | Lindner Wolfgang | Inversion of the alcohol configuration in alpha-amino alcohols via intramolecular substitution of the sulphonate groups |
| 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 |
| ZA98900B (en) * | 1997-02-07 | 1998-08-03 | Shell Int Research | Process for the manufacture of epoxy compounds |
| JP2014511365A (en) * | 2011-01-27 | 2014-05-15 | バクスター・インターナショナル・インコーポレイテッド | Use of (S) -esmolol to modulate venous stimulation associated with the treatment of cardiac disorders |
| AU2012211318C1 (en) | 2011-01-27 | 2016-08-04 | Baxter Healthcare S.A. | Methods of treating tachycardia and/or controlling heart rate while minimizing and/or controlling hypotension |
| CN102408285B (en) * | 2011-09-15 | 2013-11-20 | 东北师范大学 | Method for directly aminating benzyl hydrocarbon of methylbenzene derivative |
Citations (2)
| 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 |
| AU6628786A (en) * | 1985-12-04 | 1987-06-30 | Du Pont Merck Pharmaceutical Company, The | Synthesis of optically active aryloxypropanolamines and arylethanolamines |
-
1986
- 1986-11-14 WO PCT/US1986/002406 patent/WO1987003583A1/en not_active Application Discontinuation
- 1986-11-14 AU AU67749/87A patent/AU604005B2/en not_active Ceased
- 1986-11-14 CA CA000522978A patent/CA1282787C/en not_active Expired - Lifetime
- 1986-11-14 JP JP62500136A patent/JPS63502585A/en active Pending
- 1986-11-14 EP EP19870900373 patent/EP0248879A4/en not_active Withdrawn
- 1986-11-17 ZA ZA868713A patent/ZA868713B/en unknown
-
1990
- 1990-06-18 AU AU57562/90A patent/AU631433B2/en not_active Ceased
Patent Citations (2)
| 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 |
| AU6628786A (en) * | 1985-12-04 | 1987-06-30 | Du Pont Merck Pharmaceutical Company, The | Synthesis of optically active aryloxypropanolamines and arylethanolamines |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63502585A (en) | 1988-09-29 |
| AU5756290A (en) | 1990-10-11 |
| WO1987003583A1 (en) | 1987-06-18 |
| EP0248879A1 (en) | 1987-12-16 |
| AU6774987A (en) | 1987-06-30 |
| ZA868713B (en) | 1987-06-24 |
| AU631433B2 (en) | 1992-11-26 |
| CA1282787C (en) | 1991-04-09 |
| EP0248879A4 (en) | 1990-02-26 |
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