AROYLALKYLPYRROLIDINES CNS DEPRESSANT
May 1969
C-2 and C-9), 3.54 and 3.31 (singlets, SCHa), 2.16 (singlet, CH3COO). Anal. ( C ~ ~ H Z ~ I C, X OH, ~ )K. Reduction of 3-&uinolinol(6) in THF.-3-Quinolinol(6) (10 g ) was dissolved in T H F (I80 ml) and hydrogenated over Raney S i (K-2,9 3.0 g ) with an initial pressure of 215 kg/cm2. I t was heated to 150" during which time the pressure rose to 246 kg/cm2 and these conditions were maintained for 24 hr. After cooling, the solution was filtered through Celite and the solvent was removed in vacuo leaving 10 g of oil. Glpc indicated nearly equal quantities of trans-decahydroquinoline, trans-decahydrc-3( e)-quinolinol ( l l ) , frans-decahydro-3( a)-quinolinol (lo), and cis-decahydro-3(e)quinolinol(9). After standing, the oil solidified. A small amount of EtOAc was added, and the solid was removed by filtration and washed with EtOA4cto give 8 g of a white solid, mp 130-136". Several recrystallizations from MeOH-EtOAc gave 2 g of pure trans-decahydro-3(e)-quinolinol (11): mp 149-150 '; methiodide mp 276"; ir (CHCla), 2.77, 3.05 broad, 3.35, 3.42, 3.51, 6.92 p ; nmr (CDCIa), 6 3.65 (septet J,, = I1 cps, Jae = 5 cps, axial H a t C-3), 3.21 (eight-line multiplet J,,, = 11 cps, J., = 5 cps, J,, = 2 cps, equatorial H at C-S), 2.41 (triplet, fJom,aa= 11 cps, axial H at C-2). Anal. (CgH17SO)C, H, S. The solids, recovered from the purification of trans-decahydro3(e)-quinolinol (11) were chromatographed on silica gel (Brinkmann, 100 g ) and eluted with NeOH. d small amount of the trans-equatorial alcohol 11 was eluted first. I t was followed by czs-decahydro-3(e)-quinolinol (9) and trans-decahydro-3(a)quinolinol (10). Recrystallization of czs-decahydro-3(e)-quinolinol (9) from 1IeOH-EtOAc gave 300 mg; mp 159-160"; ir (CHCL), 2.77, 3.0 broad, 3.35, 3.42, 3.51, 6.93 p ; nmr (CDCb), 6 3.85 (septet, J,, = 9 cps, J,, = 4 cps, axial H at C-3), 3.20 (eight-line multiplet, .Jgem= 12 cps, J,, = 4 cps, J,, = 1.5 cps, equatorial H at C-2), 2.82 ( H at C-10, lt.i/2 = 9 cps), 2.49
435
(axial H a t C-2, four-line multiplet, J,,, = 12 cps, J,, = 9 cps). A a d . (CpHi7NO) C, H, N. Recrystallization of trans-decahydro-3(a)-quinolinol (10) from EtOrlc gave 200 mg; mp 95-96.5"; ir (CHCIa), 2.92, 3.34, 3.42, 3.51, 6.93 p ; nmr (CDCb), 6 3.86 ( 1 t 7 1 ~= 7 cps, equatorial H at C-3), 3.02 (six-line multiplet, J,, = 13 cps, J,. = 2 cps, equatorial H at C-2), 2.73 (four-line multiplet, J,,, = 13 cps, J., = 2 cps, axial H at C-2). Anal. (CgH17SO) C, H, K. N-Methylation of trans-Decahydro-3(a)-quinolinol (lo).-The amino alcohol 10 (1.3 g, 8.44 mmoles) was stirred nith H,CO (2.4 ml of 40% solution) in dry MeOH (40 ml) at 25" for 2 hr. SaBH4 (1.2 g) was added portionwise at 10-20 '. The solution was allowed to stir for 2 hr at 25". llezCO was added dropwise until the excess SaBH4 was decomposed. Ice was added and the mixture was extracted with CHZCL. The CHZCL solution was dried ( 11gS04)and filtered, and the solvent was removed in vacuo leaving K-methyl-trans-decahydro-3(a)-quinolinol(7) as a crystalline solid (1.39 g, 977;): mp 74-78'; nmr (CsHs), d 3.80 ( I f 11, = 8 cps, equatorial H a t C-3), 2.80 (six-line multiplet, J g e m= 12 cps, J.. = 2 cps, equatorial H at C-2), 2.07 (singlet, SCHr).
Acknowledgments.--We wish to thank Dr. E. J. Walaszek, Department of Pharmacology, University of Kansas, for the muscarinic assays and Dr. H. Higman, Department of Neurology, University of Pittsburgh, for the acetylcholinesterase studies and the nicotinic assay. The authors gratefully acknowledge support of this project by the Xational Institutes of Health Grant RG-9254 aiid GM-25,247.
Aroylalkylpyrrolidines. Central Nervous System Depressants WILLIAMJ. WELSTEAD,JR., GROVERC. HELSLEY,ROBERTL. DUNCAN,JR., ALBERTD. GALE, JR., C. ROY TAYLOR, JOHNP. DAVANZO, BERNARD V. FRANKO, AND CARLD. LUNSFORD Research Laboratories, A . H . Robins Company, Inc., Richmond, Virginia Received ivovember I S , 1968 The title compounds were prepared by alkylating 3-substituted pyrrolidines with the ketal of -pchIorobutyr+ phenones. Several compounds show CKS depressant activity comparable to chlorpromazine. Hypotensive effects were also observed in many of the compounds.
Our continued interest in drugs which affect the CNS has led us to explore in some detail the structural reqLirements for CKS depressant activity in the group of compounds generally classified as aminobu tyrophenones. This paper is the first of several which describe a series of chemical modifications beginning with the amiiiobutyrophenone I and leading to new structures with potent CYS activities.
3-anilinopyrrolidines (Table 111) which are attached to the 4 position of a butyrophenone moiety. Chemistry.-Most of the 3-aryloxy- and 3-aiiilinopyrrolidinylbutyrophenones reported herein (Tables I and 111) were prepared by alkylating the appropriate pyrrolidine with a 7-chlorobutyrophenone (protected as the ethylene glycol ketal) followed by removal of the protecting group (Chart I). By the same reaction CHARTI
n
I The work described in this paper deals primarily nith variations on the amino portion of the molecule. More specifically, our interest in pyrrolidine chemistry led LS to prepare a series of 3-substituted pyrrolidine analogs, most of which are structurally more rigid than the better studied piperidine derivatives. The compounds described herein include a group of 3-aryloxypyrrolidines (Table I), 3-acy1o:uypyrrolidines (Table 11), and (1) (a) P. A. J. Janssen in "Medicinal Chemistry," M. Gordon, Ed., Arademic Press, Inc., New York and London. 1967, p 199; (b) P. A. J. Janssen, P.
Demoen, B. Hermans. P. Van Daele, K. H. L. Schellehens. C . Vander Eychen, and C. J. E. Nremegeers, J . 1Ked. Pharm. Chem., 1. 281 (1959).
n
X
=
H, C1, F
sequence 3-hydroxypyrrolidinyl analogs were prepared aiid converted by standard methods to the acyloxy and carbamoyloxy derivatives described in Table 11. Compounds reported in Table IV were prepared from
Yield,
Fighting mouse assay ED5o. mg/kg i p , or no protected/ no. tested
%
( i n g / l q ip)
T
1%
2-OCHB J-OCHB 4-OCHS 2-OCIH, 2-0CjH.I 2-OCH7 2-OCHa 2-oCHi, 4-COCM7 4-COCH
50 36 73 s7 75
3.8 I .(i 3/3 (20) 315 (20
ti3 :J 1
leirieiitalaiialysis. 11c.activatioii ot the butyrophciionc by ketal forrnatioii6 elirniiiated both side reactions niicl inrrcasecl the yiplds of :ilkyIa t'1011 procluct Most of tlic iiovel p~rrolidiiies used iii the s> iit1ic.t I ( * sequence (Chart I) were prepared by a nucleophilic dixplacemerit reaction on a %halo- or tosSloxyp?-rrolitliii(~ (4) \T
3 Clo-r, J
l i n C h r m SOL 79, 1453 (19571 13 Hameti, .ind I . ,I McCart? [ J ai[] ( / i t (IY66)l have recent13 mplored the scope of this t > p e of relicttori (6) H. 0 . House and J. 11v r e n Blaher, %bad 23, 3'34 (19.58,
til
3 1 ?:I
437
CNS DEPRESSANT AROYLALKYLPYRROLIDINES
AIay 1969
Fighting mouse a8say
Yield, Compd
s
18 19 20 21 22 23 24 25 26
H F H
R
H H CONHCH, CONHCH3 COXHCsHs COSHCsHs CzHr COCzHj COSHC~H~CH~-VL
F H F F
F F
% 22 51 54
Recrystn solventa
Mp,
OCb
95
B-I B-I IP IP IP
140- 142 49-51 82-85 78-80 122-124 117-119 151-155 146-148 146-148
so
IP
175-1 77
70 94 90 77
75
IP IE
IE-I IE
ED,o, mg/kg ip, or no. protected/ no. tested a t 20 mg/kg ip
015 4.6 015 2.9 115 3 I5 13.2 13.5 14.1
OCH
27
F 'OCH,
a
See footnote a of Table I for solvent abbreviations.
* Melting points are uncorrected.
' HC1 salt.
Oxalate salt.
TABLE I11
Fighting mouae away
ED a, m g / k ip, or no protected/ Compd
Yield,
x
Y
H
R
%
H H
44 53 7s 68 25
Reci)ytti solvent"
R I P or bp (mm), ' C b
P
58-60
Formula
no. tested at 20 mgikg ip
CzoH22J20 1/3c CzoHz3FSzOd 115 COCzH, 230 (0.01) C23HzsN20z 015 H COC2H5 C23Hz7FS?0zd'e 0 I5 2-OCH3 H '1 120-123 CEIH d ' S 2 0 6 ' 13 hlelting points are uncorrected. 'Two animals died. Compound was purified a See footnote a of Table I for solvent abbreviations. by chromatography on a Florisil column, eluted with CsH6-31e&0. e c analyzed 0.43% low. Fumarate salt. 28 29 30 31 32
H F H F F
H H
R 1'ight:rig niouie ass8 3
No. protected/ Yield, Compd
X
Y
R
%
Kecrystii solventa
hlp or bp (mm), 'Cb
Formula
no. tested a t 20 mgikg ip
H CHI 30 200-202 (0.05) C22HmS02 0 I5 H CzHj 46 C?,H?sFN02' 2 15 35 F 4-CF3 CHI 22d 1, 106-108 CZ~H~~F~XO? 2 15 36 F 3-CH3 CdL 26e hlIK-IE 63-66 C~sHagF4~os' 2 I5 a See footnote a of Table I for solvent abbreviations. Melting points are uncorrec-ted. Compound was purified by Chromatography on a Florisil column, eluted with C6H6-hIe2C0. Prepared from an isomer mixture but only one product isomer was isolated (nmr). Oxalate salt. e Prepared from the 01 isomer. 33 34
H F
which was protected on the 1 position by a benzyl or acetyl group. Removal of the protecting group by reduction or hydrolysis, as appropriate, gave the desired intermediate (Chart II)' (Tables V I and VII). Testing Procedures.-CKS depressant act'ivit'yof t'he
compounds listed in Tables I-V was evaluated by the isolation-induced aggressive behavior test described previously by DaVanzo.8 Male albino mice mere used. Following development of the behavior, normal mice were exposed to the isolated, aggressive animals. A
( i )Some of the pyrrolidine intermediates have been reported previously hs- W , J. \\-elstead, Jr., J. 1'. DaVanoo, G. C. Helsley, C. D . Lunsford, and C. R. Taylor, J . M e d . Chem., 10, 1015 (196i).
(8) J. DaYanzo, AI, Daugherty, R. Ruckart, and L. Iiang. Psychopharmacoloyia, 9, 210 (1966).
Vol. 12
438 TABLE L' ,\IISCELLANEOUS
COMPOUNDS Fighting ~iiouseassay mg/kg r4.D~
I P , or n o protected/ 110 tested at 20 mplkg ir,
Yield,
Formula
Compd
70
Alp, OCb
3i
70
llti-119
38
58
10.9
39
60
2 3
s4
0 15
41
50
: 15
42
54
12.2
43
21
0 13
C,N,iSO
0 15
IC
,Cl-
40 CH,() ,CH
a See footnote a of Table I for solvent sb!reviations. a n d Co., Belgium Patent 668,124 (1965).
* Melting points are uncorrected.
CHARTI1
N
=
o-Ts or C1
l' = ArNH, ArO, or 110
well-directed attack on the normal animals was used as the eiitl point of the test. Blockade of this attack was regarded as evidence of depressant actioii, Tests were conducted 60 miii after drug administration. Compounds were dissolved or suspended in physiological saline. With each compound, groups of five mice were tested initially a t 20 mg kg ip. 111 those cases where aggressive behavior was prevented in all animals, additional doses were tested to allow estimation of the effective dose 50 by the statistical method of Litchfield and ITilcoxon Itepreseiitative conipounds from the series viere s t d i e d in anesthetized dogs using the procedure described in the accompanying publication.1° In ntldition, several conipouiids xwre investigated in coiiscious clogs in which hypertension developed following surgery which produced renal ischemia. l 1 Compariso115 rcportctl herein were made a t the I-mg kg iv dose level. The acute toxicity of one compound, 2, was investi(9) J Litchfield and F. Wilcoxon J. Pharmacol. Erpll. Thcrap ,!46,09 (194')) It. L. Duncan, Jr., G C Helsley, TI. J. Welstead, J r , and R V 1 i m h o J .Wed Chem 12,442 (1969). i I I j H Goldh1ntt, J L) n i h , R F Hanzal, a n d L i 11 Su~nrnerv~lle J ELIJ l f a d 59, 3 4 i (10.34) 110)
Maleate salt.
('HC1 salt.
e
Parke, Davis
gated in the mouse, rat, and guinea pig. The oral route was used in each species and, in addition, the intraperitoneal and intravenous routes were employed in the rat. Several additional tests including conditioned-avoitlance, sniphetamhe antagonism, and others were carried out on the most active compounds in this series. Some of these results will Le reported later.
Results and Discussion I t can be sceii from the pharmacological results listed in Tables I-Y that modest changes in the amino portion of the amiiiobut?-rophenone structure (I) result in significant variations in the ability of these compounds to block aggressive behavior in fighting mice. 111 the aryloxypyrrolicline series (Table 1) thc two most active conipounds, 2 ant1 5 , show EDSO's of 1.6 antl 0.7 mg kg, respectively, compared with 2.5 mg,kg for chlorprornazine and 3.6 mg, kg for haloperidol in the same test. Moving the methoxyl group around the ring (3, 4 ) , increasing the size of the alkoxy group to propoxy (6), or replacing the alkoxy group with other substituents generally reduced activity. It is intererting that the simple pyrrolidinol (19) antl its carbamate clerivative (21), both of which contain no aromatic rings on thc amino portion of the molecule, are among the most active compounds. The rcsults in Table I V show that the pyrrolidinemethanol dcrivatives (33-36) are not nearly as active as their pipericlinol relative, trifluperidol, in this test. Table T- shon-s some additional structural modifications of the active cornpourid 2 which include the valerophc~iiont38, :t I)cnzoxazepiiie 40, and tn-o ring-opeii(.(l
CSS DEPIZESSAXT ~ROPLALKTLPYKROLII)INEF~
:\lay 1969
439
TABLE 1'1 INTERMEDIATE PYRROLIDINES
c,H, c H p 3 R Compd
Yield, %
44 45 46 47 4s
67 42 50 44 45 55 29 47 43
49
50 51 52 53
/-\
OCBH~COS 0-2
\-/
Ip-IE Ip-IE Ip-112 IP IP Ip-IE Ip-IE EA-IF,
53
54 55 56
OCsH4SH2-2 OCsH4XHCOCH3-2 OC2Hj OH
34 73 63
57
-( CHz)CCsH4CF3-p OH
55
I
Recrystn solvent"
i
IP B
i\lp or bp (mm), ' C b
120-123 138-139.5 13-133 96-98 170-174 (0.13) 114.5-116.5 148.5-150.5 147-148 120.5-122 235-238 (0.1)
C22H2sS208
180-185 (0.1) 139-141 108.5-111.5
CiiHzoX20 C23H2sX206~ Ci5H2iS20dh
345-147 (0.005)
C20H22F8S01
58 -( C?Hs)CCsH4CFz-m 67 138-140 (0.07) a See footnote a of Tahle I for solvent abbreviations. llelting points are uncorrected. Fumarate salt. acterized by nmr only. 1 HC1 salt. u Precipitated from Et2O. Oxalate salt. homer mixture.
analogs 4 and 42. All of these compounds were less active than 2. The oxygen analog 43 of the known butropipazonela was inactive. F e C O C H 2 C H - C H 2 /7 N NC,,H., U butropipazone
43
I n all cases a p-fluoro substituent on the butyrophenone moiety increased the activity over that of the corresponding unsubstituted derivative. Similar observations have been noted by Janssen in related compounds.lb Certain representative compounds were evaluated in the anesthetized dog for hypotensive effects. Of the compounds tested only 43 mas essentially without effect; each of the other compounds lowered arterial blood pressure. The primary mechanism was apparently interference with a-adrenergic function. Compounds having the greatest effect 011 blood pressure (-40 to -50%) are 2, 5, 12, 27, and 32; compounds with intermediate potency are 22,23,29,37,and 38. Compounds 10, 26, and 42 decreased arterial blood pressure by less less than 20%. Keither duration of the depressor effect nor a-adrenergic inhibitory potency paralleled the degree of hypotensive action. K i t h regard to duration, 29 and 25 were the longest acting while 13 arid 38 were among the shortest acting compounds. The most potent a-adrenergic blockers include 2, 5, 38, and 42, whereas 26, 27, and 37 are among the least effective. Results obtained in studies of selected compounds in unanesthetized, renal hypertensive dogs provided confirming evidence of the hypotensive action in this series. The results in anesthetized and unanesthetized dogs were in agreement, not only with regard to the degree
C21H2aF3XO1 llaleate salt. e Char-
of hypotension produced, but also with regard to the duration of this effect. In acute toxicity studies carried out on 2, the predominant effect in three species by various routes of administration was related to impairment of CNS function. Following treatment a t the higher dose levels, effects apparent upon gross observation included catatohia, occasional mild body tremors and or mild clonic convulsions, loss of the righting reflex, flaccidity, and depressed respiration; also, ptosis and lacrimination were noted frequently. These effects were seen in the rat, for example, following intravenous doses of 12.5-15 mg kg or oral doses of 100-371 mg 'kg. Based on these and other pharmacological tests. 2 has been selected for study in human subjects.
Experimental Section The general procedures given below are representative for the preparation of the compounds described in Tables I-VII. Analyses, yields, and physical properties are recorded in the tables. Temperatures are uncorrected. Microanalyses were done by hlicroTech Laboratories, Inc., Skokie, Ill., and Spang Microanalytical Laboratory, Ann Arbor, Mich. Where analyses are indicated only by symbols bf the elements, analytical results obtained for those elements were within 3~0.4%of the theoretical values. 4- [3-(o-Ethoxyphenoxy)-l-pyrrolidinyl]-4'-fluorobutyrophenone Maleate (5).---This procedure generally gives the highest yields and cleanest products. A mixture of 10.4 g (0.05 mole) of 3-(2-ethoxyphenoxy)pyrrolidine,13.4 g (0.055 mole) of ychlorop-fluorobutyrophenone ethylene glycol ketal, and 15.2 g (0.11 mole) of K,COI in 100 ml of n-BuOH was allowed to reflux for 24 hr. After filtefing and concentrating, the residual oil was dissolved in 50 ml of Et20 and stirred with 100 ml of 3 -\' HC1 for 1 hr. The aqueous layer was separated and made basic with 3 N NaOH, and the oily product was extracted into Et2O. The Et20 extract was dried (MgSO4) and concentrated to an oil. The crude product was dissolved in CeHe and chromatographed on a Florisil column, eluting nTith C6Hs-lI&O. The purified product was converted to a crystalline maleate salt. 4-[3-(o-Methoxyplienoxy)-l-pyrrolidinyl]-4'-fluorobutyrophenone Hydrochloride (2).-A stirred mixture of 10 g (0.05 mole) of Mo-methoxyphenoxy)pyrrolidine, 9.5 g (0.05 mole) of 7-chloro-
-140
XI
I 1 3- I I7 (0.005 )'
C14 H 1 a FaS 0 See footnote a of Table I for solvent alhreviations. * Nelting points are uncorrected. " HC1 salt. ,' Jlaleate s d i . Oxaninre s:rlt. j Fumarate salt. " Over-all yield for acylation and debenzylation. Oxalate salt. ' Eased o n ixi)-step reaction froni I-:icetyl-:3pyrriilidinol. Isomer mixture (nmr 1. li From the mixture N single isomer ( a 1 TWP isiihtecl: nip 101-104'. rernwallizetl f r ~ i i i iisci~ic~t:tnc.. "
J
p-fluorobutyrophenone, and 20 g of NaHC03 in 100 nil of JIeCOi-Bu was allowed to reflux for 48 hr. The mixture was cooled arid shaken with H20 and the organic layer was dried (AIgSO,) ;tnd concentrated t o an oil. The crude oil was converted t o :i vrystalline HC1 salt. 4 4 3-Anilino-L-pyrrolidinyl)-4'-fluorobutyrophenone(281.. -.I mixture of 20 g (0.12 mole) of :j-anilinopyrrolidine, 2'2.2 g (0.1 I inole) of r-c~hloro-p-fluorol,utyrophenone, and 20 g of L C O I iii 200 In1 of dry PhJle was refluxed under S r for 3 days. The reac*tion mixture was filtered and concentrated to an oil. The oil wu.* tlisscilved i n CsHs and chromat ographed on a Florisil column using C6Ha-.\le&0 t o elute. A sample w : i ~molecularly distilled f i n
-Acetylphenoxy)-l-pyrrolidinyl]-4'-fluorobutyrophenone (10): to a stirred suspension of 4.0 g (0.01 mole) of 4-(3-phenoxyI-pyrrolidinyI)-4'-fluorobutyrophenone, 3.2 g (0.024 mole) i i f .llCIZ,and 60 ml of CS? was added a solution of 1.0 g (0.014 mole 1 of JfeCOCl in 80 ml of CS,. ;\fter the addition was complete.. the mixture was stirred and heated at reflux for 1 hr, cooled, and poured onto a mixture of ice and 100 ml of concentrated HCI. 'The CS? layer was separated and the aqueous suspension \va+ made hasir with 6 .\- S a O H . The oil which separated was t%tracted into C&, dried (AIgSOd), and concentrated. The product crystallized on standing. 4-[4-(N-Methylcarbamoyloxy )- l-pyrrolidinyl]-4'-fluorobutyrophenone (21).---.4 solution of 10 g (0.04 mole) of 1-[3-(p-fluoroi~enzoyl)propyl]-3-pyrrolidinol and 4.55 g (0.08 mole) of SIeSCO i n 100 nil of dry CsH8was allowed t o reflux under Ks for 12 hr. 'The solvent and excess 3leSCO evaporated under reduced pressure arid the resulting oil crystallized on standing. 4 4 3-Propionyloxy-l-pyrrolidinyl)-4'-fluorobutyrophenoneOxalate (25): .A mixture of 9.9 g (0.04 mole) of 1-[3-(p-fluoroIien&oyl)prupyl]-3-pyrrolidinol and 15 g of KrCOI in 100 ml of CHC1, was cooled and stirred while 4.15 g (0.04 mole) of EtCOCl dded dropwise. -1fter 15 min, 100 ml of H?O was added and qtirring was cwntinued another S O min. The CHC1, layer was qeparated, dried (hIgSOa), and concentrated t o an oil. The product wis converted to a crystalline oxalate salt. 3-[3-(o-MethoxyphenoxyJ-1-pyrrolidinyl]propiophenoneMaleate (37): -A stirred mixturv i ) f IO.(; g (0.05 mole) of 2-henzoq-l-
~thyldimerliyi~~iii~ie Iiydrochloritle. 10.1 g (0.05 mole J --!pyrrolidine, nnd 10 g of KpC03 i n 75 nil o f 11111; \vas heated at 60' for f i hr while S r w i x liuhbled t Iirou& t tic, mixture. The mixture \{-as poured into 200 nil of H.0, :itid 1 tie insoluble produc-r \vas extravted into GH6. The. C61f6(&\;I r : i v i G xere n u h e d . iirietl (.\IgSOAI. nnd cvinc,entrateti t o :in oil. The produrt WY;IP converted t o a ( 5- [3-(o-Methoxyphenoxy none Hydrochloride (38). .I misture of 1O.S g (0.056 mole) of :;-I o-inethiisypheiios!- rpyrrolitiine. 1:j.S g (0,062 mole) i d ' 6-rhlorop-fluorc,valeriiI,iienr,iie. and 16.1 g (0. I2 mole) of 1ipCO.Iin IO!) 1111 ( i f ,I-BuOH way allowed i(ireflux for 2:; hr. The niisiure W:LS filt ereti. i~onwn~fii1 ed t o :in oil< :ind rahriini:it ogr:iptiecl trii :i l~lorisilcwlunin wing C6€-16-.\le?C0t 1 1 elnic. 'The liurf' I)ro:luc-t \WP ronver1 e11 To 3 c-r? 1-[3-(o-~~etlioxyplienox~ j-l-pyrrolidinyl]-4'-j3-( o-met hoxy. phenoxy )-1-pyrrolidinyl]butyroplienone139): A sLirrcy1 misiurr of 3 g (0.00s niolc) i i f 4-[~~-io-methos~-phe1ios~~-l-py1~roli~lii1yl J4'-fluorc~i~ut~roI,henone hydroc~hloride,2 g (0.01 mole) o f :;-( 2niethos?-phenosy!pyrrolidine, :iud 4 g of I
