Note: Descriptions are shown in the official language in which they were submitted.
1SSsz8
ALKYLSULFONYLPHENOXYPROPANOLAMINES
Background of the Invention
; This invention pertains to carbon compounds having drug and
blo-affecting properties and in particular to alkylsulfonylphenoxypropyl-
amine B-adrenergic blocking agents.
According to present belief, there are at least two sub-groups
of ~-adrenergic receptors. Bl-Receptors are thought to mediate cardiac
; ~timulation and ~2-recePtors sre supposed to mediate relaxa~ion of
smooth muscle responsible for vasodilating and bronchodilating effects;
refer to C. G. Dollery, et al., Clinical Pharmacology and Therapeu~icc,
10(6), 765-799 (1969); D. Jack, The Pharmaceutical Journal, 237-240
(August 29, 1970). Various derivatives of phenoxypropanolamines reportedly
~tl have ~-adrenergic blocking properties and there can be mentioned as
representative of the state of the art, Netherlands Patent 69,0770C
(Derwent Basic No. 41,107) and Belgium Patent 762629 (Derwent Basic No.
55533S-B). The Netherlands patent, while generically disclosing
pharmaceutical prepara~ions containing a variety of substituted (including
alkylsulfonyl) phenoxypropanolamines, does not specifically disclose the
-- 1
1055S28
lass of alkylsulfonylphenoxypropanolamines of the present invention. The
Belgium patent 762629 describes a group of alkylsulfollylalkylplle-loxyprop.lno-lamine derivatives.
Summar~ of the Invention
This invention relates generally to novel alkylsulfonylphenoxy-
propylamines which possess cardioselective ~l-adrenergic blocking properties.
More particularly, the present invention provides a process for preparing a
compound selected from the group consisting of alkylsulfonylphenoxyprop~nol-
amines characterized by general structural Formula I and non-toxic
pharmaceutically acceptable acid addition salts thereof.
~ O-CH2CHCHlNH-Rl
R~ ~ R2 OH Formula I
R~
In Formula I, Rl represents a branched chain alkyl radical of 3 or
4 carbon atoms inclusive; phenoxyisopropyl or cycloalkyl of 3 to 6 carbon
atoms inclusive; R2 represents hydrogen, lower alkyl of 1 to 4 carbon atoms
inclusive; or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive; R3
represents hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4
represents hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive.
The compounds of Formula I are further defined in tllat one and only one of R2
or R4 is lower alkylsulfonyl.
Formulas Ia and Ib below and non-toxic pharmaceutically acceptable
acid addition salts thereof further characterize the compounds of the
invention.
~ O-CH C}3CH,~3-R~ ~ O-CH2CHCH,~3-R,
RSO2
R,
Formula Ia Formula Ib
_; ~ - 2 -
105SS~
In Formulas Ia and Ib, R i8 lower alkyl, R, and R, are as defined above
and only one of R, ls lower alkyl.
By the term "lower alkyl" as used herein, lt i8 meant that
the carbon chain comprising thls group lnclute both straight and branched
chsln carbon radlcals of 1 to 4 carbon atoms inclusive. Exemplary of
these carbon chain radicals are methyl, ethyl, propyl, isopropyl,
l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl. As used
herein, the term "cycloalkyl" of 3 to 6 carbon atoms inclusive is intended
to refer to any of the cycloalkyl radicals of 3 to 6 carbon atoms
inclusive such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "non-toxic pharmaceutically acceptable acid addition
6alts" as used herein refers to salts of compounds of Formula I formed
with a variety of relatively non-toxic inorganic or organic acids such
as acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic,
benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,
hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic,
p-toluenesulfonic, ant related acids. The acid addition salts of this
lnvention are prepared in conventional manner by treating a solution or
suspension of the free base in a reaction inert organic solvent with the
desired acid and then recovering the salts which form by concentration
under reduced pressure or by crystallization techniques.
Inasmuch as the compounds of general Formula I possess at least
one asymmetric carbon atom, the present invention also includes all possible
optically active forms and racemic mixture of the compounds. Resolution of
the racemlc mixtures to provlde the optically active isomers of the compounds
of Formula I i8 carried out by conventional methods relating to resolution
of phenethanolamines, for example, by salt formation with an optically
~iiSS5~8
active acit such 88 d-tartaric, tibenzoyl-d-tart~ric, d-camphorsulfonic,
d-mantelic, etc., followed by fractional crystallization.
According to the present inventlon, the alkylsulfonylphenoxyamines
of Formula I are preparet by a process which comprises reactlng a phenol
derivative of Formula II
R4 ~ R~ Formula II
wherein R2, R~ ant R4 have meanings hereinabove described with an
epihalohytrin of Formula III
CH2 CH-CH2-X
\ ~ Formula III
wherein X signifies halogen, prsferably chlorine or bromine, and condenslng
the eplhalohytrln reaction product wlth an amine of Formula IV
H~N-Rl Formula IV
wherein Rl has the meanlng hereinabove tescribet; whereafter, if tesiret,
the Formula I protuct in free base form is reactet with an acid in order
to form an acit addition salt.
The Formula II alkylsulfonylphenols are obtainet by oxitizing
the corresponding alkylthlophenols with hytrogen peroxide in accordance with
standard procedures, refer to R. B. Wagner and H. D. Zook, Synthetlc
Organlc Chemlstry, page 801 (1953 Wlley).
Slnce an epihalohydrin molecule of Formula III has two reactive
positions, reaction with a phenol of Formula II may yield a mixture of
Formulas V and VI reaction products wherein R2, R3, R4, and X are as
-- 4 --
1~555;28
defined above.
~ OC~IlCHCH~-X , , ~ OCH2CH-CH2
R4 ~ R~ OH R~ ~ d
R, R,
Formula V Formula VI
During the further course of the process, however, the two
possible intermediates of Formula V and Formula VI on condensation with
a Formula IV amine yield the same flnal product of the present invention.
Consequently, it is not necessary to effect a separation of any mixtures
of lntermediates of Formulas V and VI which may result from interaction
of a Formula II phenol with a Formula III apihalohydrin.
If desired, the epihalohydrin reaction product may be taken up
ln an inert solvent such as chloroform and shaken with excess concentrated
hydrochloric acld to convert epoxides of Formula VI into the corresponding
Formula V sulfonylphenoxyhalohydrin. Conversely, if desired, the
halohydrins of Formula V may be converted to the corresponding Formula VI
epoxide ln conventional manner, e.g., by treatment with base according to
the procedure of O. Stephenson, J. Chem. Soc., 1574 (1954).
~he interaction of Formula II phenols with Formula III epihalo-
hydrins i9 carried out employing an excess of the epihalohydrin and a
catalytic amount of a base catalyst such as N-benzylisopropylamine
hydrochloride or pyrrolidine base. Other catalysts such as pyridine,
piperidine, piperidine acetate, or piperidine hydrochloride are about
equally effective.
Interaction of Formula II phenols with Formula III epihalohydrins
can also be effected in basic med~um, e.g., sodium hydroxide, at ambient
1(3 SS528
temperatures aceording to the procedure of Y. M. Beasley, et al., J. Pharm.
Pharmacol., 10, 47-59 (1958).
Contensatlon of the epihalohydrin reaction produet with a
Formula IV amine is carried out preferably in an organic solvent
lnert under the reaction conditions, e.g., ethanol, toluene, dioxane.
The eondensation can also be effected in the absence of a reaction
solvent by using exeess amine such as isopropylamine or tert.-butylamine.
Aecording to a further feature of the present invention, an
alternate method for producing compounds of Formula I comprises reacting
a Formula II phenol wlth a compound of Formula VII in alkaline medium
CH,-/CH-CH,-N-R, Formula VII
~ R,
to provide a compound of Formula VIII
OH
~ O-CH,CHCH,N-R,
R ~ R~ R, Formula VIII
R,
wherein R" R" R, and R4 have the same meaning as in Formula I and
R~ stands for a hydrogenolysable radical such as benzyl or benzhydryl;
and converting said compound of Formula VIII to an alkylsulfonylphenoxy-
amine of Formula I. Removal of the hydrogenolysable blocking group maybe effected by catalytic hydrogenation, for example by hydroger.ation in
the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g.,
ethanol or aqueou~ ethanol.
The co~pounds of Formula VII may be obtained according to
known methods. For example, l-C(N-benzyl)isopropylamino]-2,3-epoxypropane
is obtained by reactlon of N-benzylisopropylamine and epichlorohydrin
10555Z8
in alkaline medium (e.g., aqueous potassium hydroxide) as described by
L. Vllla, et al., Farmaco., Ed. Sci., 24(3), 349-357 (1969).
A preferred group of alkylsulfonylphenoxyamines of the
preeent invention comprises compounds of Formula IX
~O-CH2CHCH~NH-Rl
~ OH Formula IX
R"
R,
wherein specific values for Rl, R~ and R4 are those defined above.
Speclflc alkylsulfonylphenoxyamlnes whlch fall wlthln the scope of
the preferred group are, for example,
l-(lsopropylamlno-3-C4-(methylsulfonyl)-m-
tolyloxy]-2-propanol,
1-(tert.-butylamlno)-3-C4-(methylsulfonyl)-m-
tolyloxy]-2-propanol,
l-(lsopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-
propanol,
1- ~ ,--butylamino)-3-C4-(methylsulfonyl)phenoxy]-2-
propanol.
A stlll further preferred group of compound~ of Formula rx
are those whereln R, i9 limited to isopropyl and tert.-butyl radicals
and R4 is limited to the methylsulfonyl radical.
Cardioselective ~l-adrenergic blocking activity of the
2~ compounds of the present lnvention can be assessed ln standsrd in vitro
pharmacologlcal tests systems such as the spontaneously beating rabbit
atrlal preparation and the guinea pig tracheal preparation. The following
Table 1, which compares potency ratios of 1-(isopropylamino)-3-C4-(methyl-
sulfonyl)-3-tolyloxy]-2-propanol hydrochloride and the clinically useful
1055SZ8
B-adrenergic receptor antagonist propranolol, is illustrative of the
cartlac selectivlty of the compounds of the present invention.
Table 1.
A Comparison of ~-Adrenergic Receptor Antagonlst Molar
Potencies Determined in Rabbit Atrial and Guinea Pi~ Tracheal Preparations
Cardio-
selectivity
Potency Ratio Potency Ratio Ratio:
ComPound Atria Trachea Atria/Trachea
10 Propranolol
l-(Isopropylamino)-3-C4-
(methylsulfonyl)-3-
tolyloxy]-2-propanol
hydrochloride 0~37 0.01 37
A preferred compound of this invention, l-(isopropylamino)-3-
[4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride, inhibits
lncreased contractile force and heart rate in the anesthetized dog
$ntuced by a standard challenge dose of 0.2 mcg./kg. (intravenous) of
lsoproterenol when intravenously administered at an ED,o of 0.71 mg./kg.
body weight and 2.02 mg./kg. body weight respectively.
Another important property of the compounds of the inventlon
is that they have llttle toxicity in mammals. With l-(isopropylamino)-3-
C4-(methylsulfonyl)-m-tolyloxy]-2-propanol hydrochloride, for lnstance,
oral LD,o values in the mouse and rat are 1504 and 1792 mg./kg. body
weight respectively; the intraper~toneal LD,o value ~n the mouse is
339 mg./kg. body weight.
Substances of the present invention represented by Formula I
are novel compositions useful in the prophylaxis and treatment of heart
diseases such as angina pectoris, cardiac arrhythmia~, cardiovascular
anxiety (neurasthenia) and hypertension. The Formula I alkylsulfonyl-
phenoxyamines are partlcularly of value in the treatment of heart dlseases
-- 8 --
1055S2~3
because they possess selective ~-adrenergic blocking activlty. Compounds
exhiblting thls selective action preferentially block cardiac inotropic
and chronotropic actlon of catecholamines such as epinephrine and
~soproterenol without greatly affecting the ~l-adrenergic receptors in
bronchial and vascular muscle.
For the purpose of exerting a cardioselective ~l-adrenergic
blocking effect, the alkylsulfonylphenoxypropanolamines of Formula I
may be administered orally or parenterally to a mammal in doses ranging
from 0.05 mg. per kilogram body weight to 20 mg. per kilogram body weight.
Preferably, the compoundQ of the inventlon are administered to a mammal
ln an effective amount sufficient to reduce the inotropic, chronotropic
effect of ~-adrenergic agonists withouth appreciably affecting the
~-adrenergic receptors in the mammalian smooth muscle tissue.
The alkylsulfonylphenoxypropanolamines of Formula I may be
compoundet and formulated with organic or inorganic solid materials or
liqulds which are pharmaceutically acceptable carriers to provide
pharmaceutical compositlons of unit dosage form suitable for administration
to mammals. Phsrmaceutlcal compositions may take the form of tablets,
capsules, powder, granules,~suspensions, solutions and the like. Suitable
pharmaceutical carriers comprise both solids and liquids such as corn
starch, lactose, calcium phosphate, stearic acid, polyethyleneglycol,
water, sesame seed oil, peanut oil, propyleneglycol, and so for.h.
Standard formulating procedures are employed to prepare the pharmaceutical
compositions.
The following examples illustrate the preparation of specific
compounds having ~-adrenergic cardioselective blocking activlty and should
not be construed as a limitation of the invention.
10555Z8
The nuclear magnetic spectral data reported herein includes the
chemical shift6 (~) In parts per million, the multiplicity for that shift
~ncludlng the coupling constant (Hz = J value) when appropriate, and the
relative area under the curve for each chemical shift which corresponds to
the number of protons. Multiplicity symbols are: s, single;; bs, broad
slnglet; d, doublet; and m, multiplet. Tetramethylsilane was used as the
internal reference.
Example 1
(a) A mixture of 4-(methylsulfonyl)-m-cresol (18.6 g., 0.1 mole),
epichlorohydrin (60 g., 0.65 mole) and 0.6 g. of pyrrolidine iB heated
on a steam bath for 12 hr. Excess epichlorohydrin is removed under
reduced pressure, the resulting chlorohydrin derivative taken up in
50 ml. of absolute ethanol and filtered through diatomaceous earth.
Isopropylamine (50 g., 0.85 mole) and 0.1 g. of potassium iodide are added
to the ethanol filtrat~ of the epichlorohydrin derivative and the mixture
iB refluxed for 18 hr. and filtered. Concentration of the filtrate under
reduced pressure affords a residue which is taken up in 70 ml. of lN
hydrochloric acid and 300 ml. of absolute ethanol. Distillables are
removed under reduced pressure and the resulting residue stirred with
ether to provide solid crude product. Crystallization of the crude
product from butanone-methanol and again from 95% ethanol-ether, affords
l-(ISOPROPYIA~IINO)-3{ 4-(~THYLSUnFONYL)-m-TOLYLOXY]-2-PROP~NOL HYDROCHLORIDE,
m.p. 177.0-179.0C. (corr.) i3 a 62~ overall yield. A sample, m.p.
176.0-178.0C. (corr), analyzed as follows.
Analysis. Calcd. for C,4H~,NO4-HCl: C, 49.77; H, 7.16;
N, 4.15. Found: C, 49.72; H, 7.16; N, 4.08.
Nuclear Magnetic Res~nance, DMSO-d 6, ~ (ppm): 1.28 Cd, 6.5 Hz,
6H~; 2.58 [s, 3H]; 3.11 [s, 3H]; 3.13 [m, 3H]; 4.11 ~m, 3H]; 7.01 Cm, 2H];
7-77 Cd, 9.2 Hz, lH~; 8.9 [bs, 2H].
--10--
1055528
(b) A modificatlon of the procedure for preparing l-(isopropyl-
amino)-3-C4-(methyl3ulfonyl)-m-tolyloxy~-2-propanol employing aqueous
sodlum hydroxlde as the reaction medium follows. Epichlorohydrin (37 g.,
0.4 mole) is atded portionwise in 5 min. to a solution of 4-(methylsulfonyl)-
m-cresol (0.2 mole) and sodium hydroxide (13 g., 0.32 mole) in 250 ml. of
water at 30C. Stirring is continued for 24 hr. and the final pH of the
solution is 8-8.5. The reaction mixture extracted with two 250 ml. portions
of chloroform, the chloroform extract dried over sodium carbonate, filtered
and the filtrate concentrated under reduced pressure provides the crude
epichlorohydrin terivative. The epichlorohydrin derivative is taken up
ln 150 ml. of ethanol and trested with lsopropylamlne (17 g., 0.286 mole)
ln 20 ml. of water. After stirring for 10 min., the mixture i8 refluxed
for 4 hr. and distillables removed under reduced pressure. The residue
taken up in ethanol and acidified with ethanolic hydrogen chloride affords
1-(ISOPROPYI~IINO)-3-L4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE.
(c) A further modi~icatlon of the procedure for preparing
l-(lsopropylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing
an eplhalohydrin derivatlve of Formula VII containing a hydrogenolyæiable
blocking group f ollows; l-C (N-Benzyl)isopropylamino]-2,3-epoxypropane
18 reacted wlth 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to
provlde l-C(N-benzyl)isopropylamino]-3- 4-(methylsulfonyl)-m-tolyloxy -2-
propanol.
The reaction mixture is filtered, acidified with ethanolic
hydrogen chloride and the benzyl bloc~ing group removed by catalytic
hydrogenation employing palladium-on-charcoal catalyst. The catalyst
ls collected and the filtrate concentrated to provide l-(ISOPROPYL-
AMINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL HYDROCHLORIDE.
1~5552~
Example 2.- Reac~ion of the chlorohydrin derivative of
4-(methylsulfonyl)-m-cresol with tert.-butylamine according to the
procedure of Example 1 ta) affords l-(tert.-BU m ~YINO)-3-C4-(METHYLSULFONYL)-
m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 175.0-176.0C. (resolidifying
and remelting at 197.0C.)(corr.)., from acetonitrile.
Analysis. Calcd. for C,5H~NO4S-HCl: C, 51.20; H, 7.45; N, 3.98.
Found: C, 50.99; H, 7.72; N, 4.20.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.31 Cs, 9H];
2.59 [8, 3H]; 3.02 [m, 2H]; 3.11 C8, 3H]; 4.10 Cm, 3H]; 6.97 Cm, 2H];
7-75 Cd, 9.5 Hz, lH]; 8.7 Cbs, 2H].
Example 3.- Reaction of the chlorohydrin derivative of
4-(metnylsulfonyl)phenol with isopropylamine according to the procedure
of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)PHENOXY]-
2-PROPANOL HYDROCHLORIDE, m.p. 193.0-195.0C., from ethanol.
Analysis. Calcd. for Cl,H2,NO4S-HCl: C, 48.22; H, 6.85;
N, 4.32. Found: C, 48.00; H, 7.02; N, 4.25.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.28 Cd, 6.5 Hz,
6H]; 3.12 Cm, 3H]; 3.14 Cs, 3H]; 4.13 Cm, 3H]; 5.91 Cd, 4.2 Hz, lH];
7.13 Cm, 2H]; 7.80 Cm, 2H]; 8.9 Cbs, 2H].
~ -- Reaction of the chlorohydrin derivative of
4-(methylsulfonyl)-o-cresol with isopropylamine sccording to the
proc~dure of Example 1 (a) affords 1-(ISOPROPYLAMINO~-3-C4-(METHYLSULFONYL)-
o-TOLYLOXY]-2-PRQPANOL as the free base, m.p. 118.0-120.0C., from
butanone.
Analysis. Calcd. for Cl4H~9NO4S: C, 55.79; H, 7.69; N, 4.65.
Found: C, 56.00; H, 7.68; N, 4.42.
~uclear Magnetic Resonance, CDCl" ~(ppm): 1.10 Cd, 6.4 Hz,
6H]; 2.27 Cs, 3H~; 2.50 [bs, 2H]; 2.85 [m, 3H]; 2.99 [s, 3H]; 4.11 Cm, 3H];
6.86 Cd, 9.3 Hz, lH~; 7.65 Cm, 2P.].
- 12 -
1055528
Example 5.- Reaction of the chlorohydrin derivative of 4-
(methylsulfonyl)phenol with tert.-butylamine according to the procedure of
Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-[4-(METHYLSULFONYL)PHENOXY]-2-
PROPANOL, m.p. 221.0 - 223.0C. (corr.)
Analysis. Calcd. for C H NO S.HCl: C, 49.77; H, 7.16; N, 4.15.
14 23 4
Found: C, 50.10; H, 7.33; N, 4.00.
Example 6.- Reaction of the chlorohydrin derivative of 4-
(methylsulfonyl)-m-cresol with cyclopropylamine according to the procedure of
Example l (a) affords l-(CYCLOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-
2-PROPANOL, m.p. 144.5 - 147.5C. (corr.)
Analysis- Calcd. for C14H21NO4S.HCl: C, 50.07; H, 6.60; N, 4.17.
Found: C, 50.23; H, 6.76; N, 4.02.
Example 7.- Reaction of chlorohydrin derivative of 4-
(methylsulfonyl)-m-cresol with phenoxyisopropylamine according to the
procedure of Example 1 (a) affords 1-(PHENOXYISOPROPYLAMINO)-3-[4-
(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 143.5 - 147.5C. (corr.)
Analysis- Calcd- for C20H27NO5S: C, 61.05; H, 6.92; N, 3.56.
Found: C, 61.12; H, 7.14; N. 3.32.
Example 8.- Reaction of the chlorohydrin derivative of 2-
(methylsulfonyl)phenol with isopropylamine according to the procedure of
Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[2-(METHYLSULFONYL)PHENOXY]-2-
PROPANOL, m.p. 187.5 - 189.5C. (corr.)
Analysis- Calcd- for C13H21NO4S.HCl: C, 48.22; H, 6.85; N, 4.32.
Found: C, 48.19; H, 7.05; N, 4.37.
Example 9.- Reaction of the chlorohydrin derivative of 4-
(methylsulfonyl)-m-cresol with cyclopentylamine according to the procedure of
Example 1 (a) affords 1-(CYCLOPENTYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-
2-PROPANOL HYDROCHLORIDE, m.p. 183.0 - 185.0C. (corr.)
Analysis. Calcd. for Cl6H25NO4S HCl: C, 52.81; H, 7.20; N, 3.85-
Found: C, 53.04; H, 7.37; N, 3.69.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm); 1.70 [m, 9H]; 2.58
[s, 3H]; 3,12 [s, 3H]; 3.15 [m, 3H]; 4.10 Lm, 3H]; 5.84 [bs, lH]; 6.94
[m, 2H]; 7.76 [d, 9.5 Hz, lH]; 9.0 [bs, 2H].
Example 10.- Reaction of the chlorohydrin derivative of
4-(sec.-butylsulfonyl)phenol with isopropylamine according to the
- 13 -
..~
10555Z8
procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(sec.-
BUTYLSULFONYL)P}IENOXY]-2-PROPANOL.
Example 11.- Reaction of the chlorohydrin derivative of
4-(lsopropylsulfonyl)-m-cresol with tert.-butylamine according to
the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-C4-
(ISOPROPYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL.
Example 12.- Reaction of the chlorohydrin derivative of
4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according
to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-
(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.
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