1710
ROBERTBRUCEMOFFETT AND [CONTRIBUTION FROX
THE
JAMES
Vol. 74
H. HUNTER
RESEARCH LABORATORIES OF THEUPJOHNCOMPANY 1
Mono- and Dimethylpyrrolidylalkyl Esters of Disubstituted Acetic Acids2
Antispasmodics. V.
BY KOBERTBRUCE~ I O F F EAND T T JAMES H. HUNTER A series of thirty-seven new pyrrolidylalkyl esters is described in which one or two methyl groups are substituted in all possible positions of the pyrrolidine ring. Some of these exhibit very high antispasmodic activity. TABLE I
R
-
I- - +
-CnHzn-N
K'
-(CHS)I 1 1 j I
or 4
CaHa
CHzCHzCH=CHCH-
-CHzCHz-NCH(CHa)
CaHa
CHzCHzCHzCHzCH-
-CHzCHz-NCH
CaHa
C€IzCHzCHzCH=CHCH-
-CHnCHn-NCH(CHs)
CHZCHZCHZ
CHzCHzCHzCHzCH-
CH&!HzCHz-
-CHL!Hz-NCH(CHa)
CHzCHzCHt
CHzCH62H=CHCH-
CHaCHzCHzCHz-
-CH~CHZ-NCH(CHS)CHZCHZCHZ
CHiCHzCHzCH=CHCH-
CHzCHzCH=CHCH-
-CH2CHz--NCH(CHs)
CsHa
CHzCHzCH=CHC€I-
-CHzCHnCH1-NCH(CHa)CHCHzCHz
C2CHzCHzCHzCH-
CH3CHzCHz-
L
,
CHzCHzCHz
(CHa)CHzCHzCHa
i
L
I
I
I
CHzCHzCHz
I
L_____i
-CHzCHzCHz-NCH(CHs) -CHnCHz-NCHzCH(CHa)
CHzCHzCHn CHzCHz
CaHa
CHzCHzCH=CHCH-
C6Ha
CHzCHzCHzCH=CHCH-
-CHzCH2--NCHzCH(CHa)CHzCHz
CHzCHzCHzCHzCH-
CH3CHzCHz-
-CHzCHz-NCHzCH(CHa)
CHzCHzCHzCH=CHCH-
CHzCHzCH=CHCH-
-
-CH2CHz-NCHzCH(CHa) CHZCHZ
CHzCHzCH=CHCH-
-CHjCH-SCHzCH(CH:)rCH,CHKHz
CsHa
CHzCHzCHzCH=CHCH-
-CHzCHz-NCHzCH(CHa)zCHzCHz
CHzCHzCHzCHzCH-
CHsCHzCHz---
CeHr CeHs
-CHzCHz--NCH(CHs) CHzCHiCH=CHCH$ I -CHzCHz-NCH(CHa) CHzCHnCHzCHzCH
CeHa
CHzCHzCHzCH=CHCH-
-CH.CH-NCH(CHa)
CHzCHzCHzCHzCH-
CHaCHzCHz-
-CHzCHz-NCH(CHs)CHzCHzCHCHa
CaHa
CHzCHzCH=CHCH-
-CH(CHs) CHz-NCH(CHa) CHzCHtCHCH
CaHs
CHzCHzCHzCH=CHCH-
-CH(CHa)CHz-NCH(CHa)CHzCHzCHCHa
CHiCHzCHzCHzCH-
CIX~CHzCHz-
-CH(CHa)CHz-NCH(CHdCHzCH9CHCHa
cas
CHzCHzCH=CHCH-
CsHa
CHzCHzCHzCH=CHCH-
CHCHEHzCHzCH-
C 1x1CHz CHg---
-CHzCHr--f:CH (CHa)CH (CHa)CHzFHr
CaHa
CHnCHzCH=CHCH-
-CHzCHz-NCH(CHs)CHzCH(CHo)CHz
CaHr
CHzCHzCH=CHCH-
-CH(CHaj CHz-NCH(CHs) CHzCH(CHs)CHz
CaHa
CHzCHzCH=CHCH-
-CHzCHz-NCHzCH(CHa)CH(CHa)CHz
CIHI
CHzCHzCHzCH2CH
-CHzCHz--NCHzCH(CHa(CH(CHa)CHz
CIHK
CHnCHzCHzCH=CHCH-
-CHiCHz--NCHzCH(CHa)CH(CHajCHz
CHsCHzCHaCH:CH-
CHdCHzCHz-
-CHzCHz-NCHzCH(CH:)CH(CHsj CHZ
CHzCHtCH-CHCH-
CHzCHnCHzCHi-
-CH~CHz-NCHzCH(CHs)CH(CHs)CHn
I
-____i
2
CHzCHz
CaHs
CHzCHzCH=CHCH-
-CHzCH?-NCH(CHa)zCHzCHzCHz
CaHa
CHzCHzCHzCHzCH-
-CHzCHz-NCH(CHa)zCHtCHlCHzCHz
CaHs
CHzCHzCHiCH=CHCH-
-CHiCHz-NCH(CHa)zCHzCHzCHz
CHzCHzCHzCHCH-
CHaCHzCHz-
-CHzCHs-NCH(CHa)zCHzCHzCHz
CHzCHzCHzCH=CHCH-
CHzCHzCH=CHCH-
I
,
I
CsHa
1 I
I
- 1
-
I 1 i J
I
CHzCHzCHCH: CHiCHzCHCHs I
I
I
-
I
CHzCHzCHCHa
-CHZCHZ-NCH(CH~)CH(CHI)CHZCHZ
I
1
I
i
I
, I
L____i
In continuation of the study of the relationship of structure to antispasmodic activity and in view (1) The fourth paper i n this series is: R. R . Moffett, J. 1% Hunter and E. H. Woodruff, J . Org. Chem., 15, 1013 (1950). (2) Reported before the XIIth International Congress of P u r e and Applied Chemistry, h'ew York, N. Y., September 10-13, 19.51.
of the high activity of some of the pyrrolidylalkyl esters previously r e p ~ r t e d it , ~ seemed desirable to prepare a number of such esters substituted on the (3) H. G. Kolloff, J. H. Hunter, E. H. Woodruff and R. B. Moffett, THISJOURNAL, 70, 3862 (1948); ibid., 71, 3988 (1949); H. G. Kolloff, J. H. Hunter and R. B. Moffett, ibid., 73, lG50 (1950).
April 5, 1952
METHYLPYRROLIDYLALKYL ESTERS OF DISUBSTITUTED ACETICACIDS
pyrrolidine ring. In this paper are reported esters in which one or two methyl groups are substituted in all the possible positions on the pyrrolidine ring disregarding stereoisomeric forms. The esters were prepared by methods previously described'~~ and are listed in Table I.
88.2
B.p. ' C . Mm. 150 0 . 2
Empirical Nitrogen, % Yield, formula ~ Calcd. Foundb 1.5197 CzaHzrhTOz 4.47 4.67 82.8
90.6
125
.02
1.5130
90.6
134
.03
90.0
89
85.4f 81.3
1711
The requisite methyl-substituted pyrrolidyl alcohols were recently reported4 except for 2-(2,2dimethyl-1-pyrrolidy1)-ethanol,the preparation of which is to be included in a separate communication. The disubstituted acetic acids are for the (4) R. B. Moffett, J. Org. Chcm., 14, 862 (1949).
v,p2
Empirical Chlorine, % ' formula Calcd. Foundb CzoHzaClNOz 10.13 10.19
Antispasmodic activitye 0.7
126-128.5
Crystallizing solvent EtOAc
C ~ H Z P N O Z4.44
4.39
80.4
133-136
MeEtCO
1.5248 CziHzsNOz
4.28
4.20
76.1
146-148
MeEtCO
.02
1 .4672
Cir HaiNOz
4.98
4.77
93.2
119.5-120.5
EtOAc
103
.02
1.4735
CisHaiNOz
4.77
4.72
92.0
130
.02
1.5022 CzoHniNOz
4.41
4.41
..
107-110
EtOAc
CzoHazClNOz 10.02 10.06
.1
89.6
132
.Ol
1.5169
CziHzeNOz
4.28
4.47
83.3
166-167
EtOH f EtOAc
CziHaoClNOz
98.0
117
.03
1.4674
CiaHaaNOz
4.74
4.83
82.0
167-169
97.0
121
.Ol
1.5238 CzoHzrNOz
4.47
4.54
60.8
102-106
93.5
133
.Ol
1,5238 CziHzeNOz
4.28
4.22
57.0
120-123
94.5
87
.Ol
1.4660
CiiHaiNOz
4.98
4.99
83.0
96.5-98
83.4
126
.01
1.5012
CzoHaiNOz
4.41
4.39
94.7
99-100
4.29
83.4
132-142
Yield,
%"
~
2
5
98.5-100
+ EtOAc
CzoHaoClNOz 10.08 CziHaoClNOz
+ Et20 EtOAc + EtzO
CiiHazClNOz
9.74
.8
10.06 9.54
.7
11.16 11.15
1.0
CisHazClNOz 10.75
0.3
10.65
9.74
9.68
.1
EtOH
CisHsaClNOz 10.68
10.65
.1
EtOAc
CzoHzaClNOz 10.13
9.97
.1
CniHsoClNOz
9.74
9.60
.1
CirHazClNOz 11.16
11.24
.1
CzoHszClNO, 10.02
9.86
.1
9.74
9.82
.7
9.63
.8 .2
+ EtOAc + Et20 EtOAc + Et90 EtOAc + Et90 EtOAc + Et20
89.6
125
.Ol5
1.5177 CziHz9NOz
4.28
EtOAc
CziHaoClNOz
74.0
140
,065
1,5109 CziHaiNOz
4.25
4.34
91.0
110-112
EtOAc
CziHarCINOz
9.69
87.9
134
.014
1.5227
4.10
4.12
67.5
187-158.5
MeEtCO
CzzHazClNOz
9.38
9.45 10.75
1.2 0.9
CzzHaiNOz
76.0
100
.03
1.4679 CisHasNOz
4.74
4.72
88.9
119.5-121
EtOAc
CisHaaClNOz 10.68
64.6
128
,013
1.5011
4.23
4.32
73.0
130.5-132
EtOAc
CziHaiCINOz
9.64
9.66
92.2
133
.04
1,5179 CziHzeNOz
4.28
4.27
89.5
116-1 18
EtOAc
CziHaoClNOz
9.74
9.73
92.2
134
.01
1.5180
CzzHaiNOz
4.10
4.26
84.5
131.5-133.5
EtOAc
CzzHazCINOz
9.38
9.41
81.9
102
.04
1.4631 CisFI3aNOz
4.74
4.80
72.2
107.5-108.5
EtOAc
85.5
131
.02
1.5153 CziHzeNOz
4.28
4.41
67.5
117.5-122.5
EtOAc
CziHaoClNOz
9.74
9.77
.6
92.3
138
.06
1.5089 CziHaiNOz
4.25
4.23
59.2
135.5-136.5
MeEtCO
CziHazClNOz
9.69
9.53
.3
90.2
145
.03
1.5202
CzzHaiNOz
4.10
4.15
63.6
123-128
MeEtCO -I-EtOAc CzzHazClNOz
9.38
9.02
.6
81.2
113
.07
1.4657 CisHaaNOz
4.74
4.90
90.6
116-120
EtOAc
CiaHsCINOa
68.0
124
,015
1.5097 CzzHaiNOz
4.10
4.11
44.0
143-146
EtOAc
CzzHazClNOz
77.1
154
.05
1.5147
CzaHaaNOa
3.94
3.95
..
65.9
117
.03
1.4636
CivHasNOp
4.53
4.61
..
80.5
138
.03
1.5170 CziHzeNOz
4.28
4.46
87.0
105-107.5
EtOAc
89.0
151
.04
1.5219
CzzHaiNOz
4.10
4.19
58.6
145-156
MeEtCO
75.7
109
.03
1,4670 CisHiaNOz
4.74
4.72
88.3
101-104
EtOAc
132
.02
1.5147 Czt HzsNOz
4.28
4.26
80.0
150-152
MeEtCO
121
.m
1,5078 CzzHaiNOz
4.10
4.10
20.0
136-140
EtOAc
93.5
126
.015
1.5133
CZIH~PNOZ4.28
4.28
..
91.6
125
.Ol
1,5065 CziHaiNOz
4.25
4.22
..
90.3
142
.02
1.5180 CzzHsiNOz
4.10
4.08
72.0
122.5-124
EtOAc
CazHazClNOz
9.38
9.41
.01
86.5
95
,025
1,4634 CiaHaaNOz
4.74
4.74
93.5
143-145
EtOAc
CisHaiClNOa 10.68
10.50
.01
85.0f
124
.04
1.4696 CisHaaNOs
4.56
4.65
94.7
136-137.5
EtOAc
CieHsrCINOs
10.41
.. ..
CziHaaNOz
, . . ...... .........
.........
.........
+ EtzO + EtzO
CisHarCINOz 10.68 10.65
+ EtzO
.01
