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Патент USA US3086031

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United States‘ Patent ‘0”
1
,
3,086,021
3,086,021‘
Patented. Apr. 16, 1963
2
,
'
amine with sodamide at the re?ux temperature of an
inert solvent such as benzene.
v
TERTIARYAMINO BUTYNYL ALCOHOLS
John ‘H. Biel, Milwaukee, Wis-,assignor, by rnesne as
The reaction is preferably carried out by contacting
No Drawing. Filed Sept. 20, 1957, Scr. No. 685,091
10 Claims. (Cl. 260-268)
the reactants in the presence of an inert solvent, such as
benzene or toluene, and. employing an elevated tempera
ture, such as the re?ux temperature, to effect reaction in
‘a convenient“ amount of time. The desired product may
This ‘application is a continuation-in-partof my ap
are
signments, to Lakeside Laboratories, Inc., Milwaukee,
Wis., a corporation of Delaware
.
be recovered from the reaction mixture by conventional
This invention is related to acetylene compounds. More
procedures such as cooling the mixture as over ice and
particularly, it is concerned with novel 4-amino-2-butynes 10 ‘?ltering off the product.
and methods of producing such compounds.
Some typical novel compounds produced by this method
plication Serial No. 602,527, ?led August 7, 1956 now
abandoned.
1—phenyl- 1- (4-pyridyl) -4-diethylamino-Z-butyne-1-01,
‘
There are provided according to the present invention 15
‘novel 1',l-dicyclic - 4 -. disubstituted .amind-Z-butyne-l-ol
l-phenyl- 1- ( Z-thienyl) ~4-morpholino-2-butyne-1~01,
compounds of ‘the formula
, l-phenyl-1-fuIy1-4-dimethylarnino—2-butyne-1-ol,
20
l-phenyl- 1- (4-pyridyl) -4-pyrrolidino-2-butynee1-o1,
l-phenyl-l- ( Z-thienyl) -4- dimethylamiuo-Z-butyne-l -ol,
l-phenyl- 1- (Z-thienyl) -4-diethylamino-2~butyne-1~01,
l-phenyl- 1 - (Z-thienyl) -4-pyrrolidino-2-butyne- 1 -ol,
and acid addition and quaternary ammonium salts thereof,
wherein R1 is a phenyl or nuclear substituted phenylgroup
such as a lower .alkoxy ‘phenyl, lower alkyl phenyl, hy
d-roxyphenyl or halophenyl ‘group, or a thienyl, pyridyl,
or lower cy'cloalkyl group such'as cyclohexyl or cyclo~
pentyl, and R2 is a thienyl, pyridyl or furyl group, R3 ‘is
1-cycl-ohexyl-1-(2-thienyl ) -4-diethylamino-2—butyne-1-ol,
' 1-cyc1ohexyl-1-(2-thienyl ) -4-pyrrolidino-2—butyne—1-ol,
1 - ( Z-thienyl) ~4-diethy1amino-2-butyne-1-o1,
25 l-cyclopentyll-cyolop entyl- 1- ( Z-thienyl) -4-pyrrolidino-2.-butyne~l-ol,
l-phenyl-1-(4-pyridyl) -4-dimethylamino-2-butyne-1-01,
1, 1- (4-pyridyl ) -4-diethylamino~4-ethyl-2-butyne-l-ol,
1,1-bis(2-thienyl) -4-pyrrolidino-2-butyne-l -ol and
same or different alkyl groups, preferably lower alkyls," 30 l-cyclohexyl-l- ( 2-thienyl) ~4- ( 4’-methylpiperazino) -2,
" hydrogen or a lower alkyl group and R4 and R5 are the
butyne- 1 e01.
" aryl groups, preferably monocyclic aryl groups such as
the phenyl group, aralkyl groups, preferably lower alkyl
monocyclic aryl groups like benzyl and phenethyl groups,
alkeny-l groups, preferably lower alkenyls such as the allyl
Acid addition salts of these and other such compounds
as are included within the scope of this invention may be
produced by contacting .the {compound with a suitable
group and groups in which R, and R5 are joined to form‘ 35 acid suchas a mineral acid like sulfuric acid or hydro
a heterocyclic ring, preferably of 5 or 6 atoms in the
chloric acid or organic acids like maleic acid, fumaric
ring such as pyrrolidino, piperidino, piperazino and
acid, acetic acid and citric acid.
morpholino.
Quaternary ammonium salts mayalso be readily pre
These compounds, as the bases, may be conveniently
pared by contacting the compounds‘with alkyl and aralkyl
“ produced‘ by reacting an appropriate dicyclic ketone with 40 esters'of mineral and organic acids, preferably in the
a reactive metal salt, such as an alkali metal ‘salt, of an
appropriate tertiary aminopropyne. This process may be
‘ represented as follows:
. presence of a suitable organic solvent. Alkyl halides such
as methyl bromide, ethyl iodide, methyl sulfate, benzyl
‘
chloride and propangyl bromide are representative com
pounds that may be used to form quaternary ammonium
salts.
In the form of non-toxic acid addition salts the novel
amino butynols are sedative and diuretic agents. The
‘non-toxic quaternary ammonium salts of these compounds ‘
are potent gastric anti-secretory agents useful in the
wherein A is a reactive metal and R1, ‘R2, R3, R4 and R5
have the signi?cance assigned above.
Representative dicyclic ketones which may be‘empl-oyed
therapy of peptic ulcer; in addition, they are potent
antispasmodics, useful in relieving disturbances of the
digestive tract. ‘
“ in‘this reaction are 4-methoxyphenyl 2-thienyl ketone, 2
' The following examples illustrate speci?c embodiments
of the invention, but it is to be understood that these ex
amples are for illustration only and are not to be con
sidered as restricting the invention.
ethylphenyl 4~pyridyl ketone, 4-hydroxyphenyl Z-thienyl
"ketone, phenyl 2~thienyl ketone, cyclohexyl Z-thieny-l
ketone, cyclopentyl >2~thieny1 ketone, phenyl 4-pyridyl‘
' ketone, phenyl‘furyl ketone and di-(2-thienyl) ketone.
Typical tertiary amiuopropynes such as 3-dimethyl
EXAMPLE 1
amino - 1 - propyne, S-diethylamino-l-propyne, B-pyr
‘ rolidino-l-propyne,‘ 3-N-morpholinyl-1~propyne,. 3-piperi 60
' dino-l-propyne, 3‘-diphenylamino-1-pnopyne, 3-diethyl
amino-3-methyl-1-propyne, and S-dibenzylamino-l-pro
pyne ‘may be employed in the reaction in the form of re
active metal salts such as the alkali metal salts. The
sodium salts are readily prepared by reacting the propynyl
65
1 -CyclohexyZ-1 (Z-Thienyl) -4-Dimcthylamina-Z-Buiyne
1-0l
To 7.8. g. i(0.2.mole) of sodamide in 75 cc. of benzene
'was added 17 g;'(0.2 mole) of dimethylamino propyne
and the mixture heated at re?ux for 1 hour. Then 38
g. (0.2 mole) of cyclohexyl Z-thienyl ketone was added
3,086,021
and the mixture re?uxed for 6 hours. It was poured over
ice and the solid which formed collected on a ?lter. The
ing the appropriate reactants, the bases of Table 1 were
prepared.
TABLE 1
R1\(I)H
0-050-0117451
R2
Assay
R1
R:
Am
M.P.,
Yield,
° 0.
percent
Caled.
Found
Percent Percent Percent Percent
N
N
—N(OH5)7 ____ ._
134-136
CH
74
5.10
11.55
5. 08
11.00
84
80
03
87
81
35
4. 00
4.71
5.05
4. 59
4.52
5. a2
1o. 74
10.77
11.55
10.49
10.55
12. 16
4. 32
4.74
4.83
4.57
4. 33
(1)
10.84
10.25
11.45
10.48
10.00
(I)
—-N (041105.
Pyrrolldino
86
90
4.81
4. 84
—-N (0114):.
95
10.52
10. 09
11. 07
______ ._
(1)
0)
(1)
(1)
10.18
...... ._
1 Bases not isolated.
product was recrystallized from hot n-hexane. MI’. 135
136° C.; 51 g. (93%).
In Table 2 there is set forth various data concerning
quaternary ammonium salts of typical bases that have
Analysis.-Calcd. C16H23NOS: 5.05% N; 11.55% S.
been prepared.
Found: 4.83% N; 11.45% S.
TABLE 2
B1 OH
/(IJ-—OEC——CHQAID.R3+X'
R2
Assay
R1
R1
R5
Am
X
M.P.°C Yield,
Calcd.
percent
Found
Percent Percent Percent Percent Percent Percent
N
S
X
N
S
X
Phenyl_.___ 2rthienyl____ CH;— —N(OH5)1-.__ Br
D
__ CH5—-
202-203
—-N (071192... Br
CH3——- Pyrrolidlno.-. I
CH;- —N(CH4)1--.- I
CH;- —N(C4H1)5.-_ I
_ CH:-
89
3.82
8.74
21.85
3.85
8.85
22.17
160-161
87
3. 55
8.12
20.36
3.57
8.16
20.69
143-144
175-177
106-168
94
93
90
3.19
3.34
3.13
7. 29
7.63
7.16
28. 93
30.31
28.41
3.04
3.79
2.93
7.24
7.54
7.20
30.05
29.47
28.14
28.51
Pyrrolidino.-. I
146-148
94
3.15
7.19
28. 53
2.95
7.22
0115- —N(OH5)4____ I
150-152
80
3.45
7.90
31.35
3.27
7.97
30.48
CH;- —N(C1H5)5_-_ I
CHT" Pyrrolidino... I
110-112
105-107
85
86
3.23
3.25
7.30
7.42
20.33
29.46
3.01
3.08
7.58
7.42
28.00
29.61
Table 3 sets forth data for bifumarate and fumarate
EXAMPLE 2
salts of typical bases provided by this invention.
By following the procedure of Example 1 and employ
TABLE 3
R1 (‘>11
C--OEO—-OH4Am-HOOO—CH=CH—~OO0H
Ra
[“]3l£umarate”]
Assay
R1
Cyclopentyl ..... -D0 .... __
._
R2
Am
_
M.P.,
°C
Yield.
per
Caled.
Found
cent
Per-
Per-
Per-
Per
cent
cent
cent
eesnt
—N(CH5)2 .... -_
-——N(C:H5)z..-_..
125-126
120-123
83
80
3.69
3.44
8.44
7.86
3.06
3.36
8.26
7.12
Pyrrolidln0_-.__
130-132
90
3.46
7.90
3.35
7. 83
3,086,021
6
R:
R2
[“Fumarate”]
Assay
Yield .
per
cent
Per
cent
195-196
175-177
216-217
Z-thienyl ______ -.
___-.do _______ ._
4-pyridyl ______ -_
Example 3
group consisting of phenyl, lower alkoxy phenyl, lower
I -Cyclohexyl-1 ~ (a-Thienyl) -4->(4'-Methyl-Piperazino) -
alkyl phenyl, hydroxyphenyl, hlalophenyl, thienyl, pyridyl,
Z-Butyn-I-ol
‘and lower cycloalkyl groups, R; is :a member of the group
consisting of thienyl, pyridyl, and fury], R3 is a member
of the group consisting of hydrogen and lower alkyl
groups, and R4 and R5 are members of the group con
sisting of lower alkyl, phenyl, phenyl-lower alkyl and
‘lower alkenyl groups, and groups in which R; and R5 are
joined to form a heterocyclic ring of the group consisting
of pyrrolidino, morpholino, piperidino and piperazino
Cyclohexyl 2-thieny1 ketone was reacted with 3-(4'
methylpiperazino)-1-propyne as the sodium salt as in Ex 30
ample 1 to form this compound.
M.P. 133-135° C. Analysis.—-Calcd. for C19H28N2O‘S:
N, 8.43; S, ‘9.63. Found: N, 8.15; S, 9.64.
groups.
01.
3. l-phenyl-l-(Z-thienyl)-4-diethylamino-2-butyne-l-ol.
4. 1-phenyl-1-(2-thienyl)-4-pyrrolidino-2-butyne-1-ol.
5. 1-cyclohexyl-l-(2-thienyl)-4-diethylamino-2-butyne
The mono-methiodide salt melted at: 190-192° C.
Analysis.-—Calcd. for C20H31IN2OS: N, 5.90‘; S, 6.75; I,
26.79. Found: N, 5.62; S, 6.64; I, 27.25.
The dimethiodide salt melted at: 204-206“ C. Anal
ysis.—Calcd. for C21H34I2N2O‘S: N, 4.56; S, 5.21; I, 41.36.
Found: N, 4.23; S, 5.07; I, 40.87.
.
2. l-phenyl- 1-( Z-thienyl) ~4-dimethylamino-2-butyne-1
35 l-ol.
6. l-cyclohexyl-l-(Z-thienyl)-4-pyrrolidino-2-butyne-1
ol.
7. l-cyclopentyl-1-(2-thienyl)-4-diethylamino-Z-butyne
The mono-fumarate salt melted at: 168-169 °, C. Anal 40 1~ol.
)’SiSr-C31Cd. for C23H32N205S: N,
N, 5.85; S, 6.74.
S, 7-14. Found:
I
8. l-cyclopentyl-l-(2-thienyl)-4-pyrrolidino-2-butyne-1
ol.
9. 1-cyclohexyl-1-(a-thieny1)-4-(4’-methylpiperazino)
Various changes and modi?cations of the invention can
Z-bu-tyne-l-ol.
be made and, to the extent that such variations incorpor
10. 1 - pheny1-1-(4-pyri-dyl)-4-dimethylamino-Z-butyne
ate the spirit of this invention, they are intended to be 45
1-01.
included within the scope of the appended claims.
What is claimed is:
References Cited in the ?le of this patent
1. A member of the group consisting of compounds
UNITED STATES PATENTS
of the formula
2,680,115
2,782,191
Ruddy et a1 ____________ __ June 1, 1954
Reppe et a1 ____________ __ Feb. 19, 1957
OTHER REFERENCES
Fieser et al.: Organic Chemistry, pages 86-87, second
and non-toxic acid addition and non-toxic quaternary am
monium salts thereof, wherein R1 is a member of the 55 edition, 1950.
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