Jocund of Xedzcinal Chetmstry, 1970, Vol. 13, .\ 0. 5 871
4-Hr U K U X ' ~Q U I X U L I EC.~ILBOXY ~ IA'I LS
SCHEME I1
OH
OCOR
OH H., Pd
2 AICI, Fries rearrangement
NHAc
(AcOHJ
NHAC
In other examples the synthesis of 6,7- and 7,8-disubstituted 4-hydroxy-3-quinolinecarboxylates is shown in Scheme 111.
OCOR
a OR
5H.k
OK
OBz
OH
fumingHh'0,
(AcOK Ac,O)
sapmifica lion
+
I NO,
9
OR
H, PtO. __f
OH
OR
C0,R"
250 Dowthern, A
R'O I
4.5
NHCH=C(CO,R"), 11
6a-lla, R =
L o -
R = Cr&+,O6b-llb, R = CnH2"+,0K'=
L o -
X = C1 o r Br (See Experimental Section)
Claisen rearrangement of m-allyloxyacetanilide was reported by Arnold and coworkers4 to give 19. Nore recently, however, BudGinskjr and Rofkovaj showed that 20 is formed as a side product. We found that the two isomers were produced, with 19 predominating; they were separated by fractional precipitation of the phenols from a mixture of the Na salts. Conventional synthetic methods then gave 24 and 29. Biological Results. A.-As a primary screening method compounds were tested against one species of coccidia (Eimeria tenella) as folloivs. One-day old Leghorn chicks, purchased from Shamrock Farms, Korth Brunswick, S.J. 80902,were kept in electric brooders for 7 days. They were then divided into appropriate experimental and control groups comprised of 5-10 birds each and placed into cages heated with light bulbs. The 8-day old chicks were inoculated into their crops with approximately 2 X lo5 sporulated oocysts of E . tenella by intubation. One day prior to infection the regular starter feed was replaced by medicated diet consisting of feed with the drug incorporated by mixing in a rotating V-shaped mechanical mixer. Compounds were tested initially at 0.05yodose level in the feed. In the event of positive coccidiostat activity the dose level was reduced in subsequent experiments to determine the minimnl coticentr:itior~ exhibiting anticoccidial efficacy. Death from coccidiosis among UII( 4 ) R . T. Arnold .J. hIc('w1, a i d E. SctlulrL, . J . A I I W ~ L. ' h l . n t . , s u r , . , 6 4 , 1025 (1942). (5) Z. UudGinskf a n d E. R d k o v a , Chem. L i a t y . 48, 4 2 i ( l 9 , 5 i j ; Chem., Abstr., 49, 3880c (1955).
872 J o i ~ r r ~ uojl Xedicinul Chemistry, f!ii'O, b'ol. 1.1, LYo. :i
I
s1111' I
11
Journal of Medicinal Chemistry, 1970, Vol. 13, No. 6 873
4-HYDROXYQUINOLINECARBOXYLBTES
T ~ LI E(Continued) Pro-
Yield,
Rs
cedure
76
NHCH=C (C02E;t)z NO2 NHCH=C (C02Et)Z
N
M p or bp " C (mm)
Analyses
Notes
C, H, N (ir, nmr)
r\;
7 5 . 8 135-138 5 0 . 8 113-114 8 5 . 0 107-108
NO2
L,
4 7 . 7 104-105
C, H, X
so2
E
76.9
73-75
N (ir)
NHCH=C (C0& t )z
N
93.2
55-56
C, H, N (nmr)
NO2
Y
95.0
87-90
c, H, N
SHCH=C(COzEt),
N
so2
E
59.7
63-64
N (ir)
NHCH=C (CO&t),
x
85.0
30-31
C, H, K (ir)
so2
E
80.0
91-92
C, H, N (ir)
NHCH=C(C02Et jz
9
NO2
E
NHCH=C(CO&t j 2
N
NO,
E
72.0
59-61
C, H, N (nmr, ir)
XHCH=C(C02Et)2
K
95.0
41-43
1"(
NHCH=C(C02Me)2
N
Oil
(Kmr)
a
KO,
E
Amorphous
(IF)
a
NHCH=C(COzEt)?
r\;
Oil
(Nmr, ir)
a
NO2 NHCH=C(C02Et)2
E
NO2 NHCH=C (CO&t)?
E N
69.0
Quant 56-57
C, H, N (ir) C, H, N (nmr)
AuNH
E
52.3 128-129
K(nmr)
NHCH=C(CO&t j1 AcNH AcNH BcNH
N H I
J
87.9 124-125 8 4 . 0 43-45 55.0 105-107 61.0 120-123
C, H, N C, H, N N (nmr, C, H, S
-4cNH
K
Oil
("r)
a
NHCH=C (COJEt)2
T
Quant Oil
("r)
a
NH2
S
Oil
(Ir)
a
w
Oil
a
Oil 93.5
81.2
a Material carried through to next step without further purification. of one component. d 98.4y0 purity by glpc. e 99.374 purity by glpc.
a
48-49
Oil
IL'
medicated control birds started about 4 days after infection; by day 9, 90% or more were dead. For evaluation of coccidiostatic activity, the cumulative mortality on day 8 after infection was determined in control and treated birds. An 80% protection was considered a marked coccidiostatic effect. B.-A more rigorous efficacy test against a mixed coccidial infection was carried out in battery cages on compounds with activity against E. tenella. One-day old Peterson Cross (Peterson males x Arbor Acres females) broiler chicks obtained from a commercial hatchery were raised in battery brooders for 2 weeks
C, H, N ( n m ) C, H, N (nmr)
61-62 Dark oil 63-64
a
HJ
"r)
a
) r"( (Nmr)
Glpc analysis indicated 99% purity.
a
a
(nmr, ir) (ir) ir) (ir)
TICindicates preaence
before the test. Ten birds, 5 males and 5 females, were randomly selected for each group. The treatments were replicated 2, 3, or 4 times. Feed was available to the chicks ad libidum. The medicated feed was offered starting 2 days before infection, the only feed throughout the trial period. The coccidial inoculum was prepared by mixing a calculated number of sporulated oocysts from pure cultures of E . acervulina, E . bwnetti, E. maxima, E. necatrix, and E . tenella. The inoculum was administered into the crop to each individual chick with an automatic pipettirig syringe equipped with a S o . 7 venous cannula. The criteria of anticoccidial
23
SI I
24
SI I.\[
27
26
28
29
;tctix.ity w r c ~weight gain, f e d conv~rsioii.mrvival, fwal dropping score, arid oocyht output.
Discussion of Biological Results
'I%(> beriehcial results rioted for ethyl ti,'i-bis(r\ cloi)rol)ylmethoxy.)-.Z- hydroxyquinoline-3 -carboxylat (cyproquinidate) were increaved substantially b>- wplacement of one of the ether groups by a long-chain :dkoxy substituent. The greatest effect was attainrd with ethyl 6-c~cloprop~lmethoxy-'i-decyloxy-4-h~ clroyxquinoline-3-carboxylate (83, Table 111),although t h e 7-octyloxj (81) and 7-dodec~-loxy(84) were almost a s active. X less beneficial effect wah noted with the 7 cyclopropSlmethoxv-fj-dec.loxy isomer (88). .inticoccidial activity wa. also demonstrated for t,t hyl 7-butyl-6-cyclopropyln~ethoxy-4-hydrox~ quiriolin~.-:3-carboxylate (95) , the F-butyl-7-cyclopro~~~lmethoxy compound, however, waq less active than i t < ihomw. I J u r t h t ~ m o r eun\utur:ition , in t h e alkyl group (92) or irttroductioii of an oxo function (100) lead to :i decrease in activity. Shifting the carbethoxy grouping to the 2 positiori i101, 102) w ~ cletrimrntnl s to the nnticoccidixl effect I iit~tlic~r~noi~c, moviiig t h e G-:tll~ylto t h e \ lwitioil I ~ ~ i t l to :i t1ccre:tsc i n uctivit! (3
Journal of dledmnal Chemistry, l9?0, Vol. 13, .Yo. 5 875
TABLE I1 QH
Yield,
Ka
ho.
‘lo
Et0
79.6
390-290.5 dec
71
11eO
52.0
269-272 dec
72
Et0
69.4
299-302
63.9
265-268
66.4
293-294 dec
7ti
40,0
1S3-lS4
7ti
33.2
2b0-2b5 dec
73 74
0
Alp, o c
70
El0
77
NHSH:!
j5.6
265-267 dec
78
Et0
70.8
273-373 dec
79
Et0
so
Et0
74.6
269-270 dec
SI
Et0
34.3
236-235
h3
JleO
16.0
333-234
h3
Et0
64.5
233-234
54
27.5
2 10-2 13
S.i
60.0
337-238
S6
55.9
294-293 dec
hi
23.3
325-3217
8b
26.1
234-233
h9
35.1
23S-2b7 dec
00
36.4
292-1293 dec
285
01
LLO
45.4
292-393
92
Et0
rdd
- _. 0
2c):l-39.j
9:i
11.4
2.1.1
94
61.7
9 r,
65.0
237-239 dec 239-261 dec
96
-., I .I.0
2%
97 9Y
SO.O
287-2’39 dec
99
63.9
100
77.8
.i7 , 3
311-313 dec >390 398 3-299 dec
All compds were analyzed for C, H, S .
control was efl‘evted bvith nil ice -water bath. Stirring was contiriiied for 4 I n ut i’oom temperatiire. The mixtiire was washed w i t h ‘LOO ml of 2c/i S:LOIIa i d ‘LOO in1 of ilrO. The dried extriict was stripped of solveiit and the oily residue distilled, b p 152-155” (0.4 mm) (27.8g).
Procedure C.
2-Cyclopropylmethoxy-5-nitrophenyl Benzoate.
mix to a mixtiire of 75 ml nf fuming HNO:, :tiid 1100 ml of .kcOH ~ Y U Y added di,op\vihe with efficieiit stirriiig a rolutioti o f 78 g of o-cyclopropylmethoxypheiiylbenzoate in 75 ml of h c 2 0 . Diiriiig the addition (15 min) the temperature rose to 55’. After 5 hr
.\.A 2 T I V I T l . Liised i n i e ~ t i u n
~
( 'oncentra-
i i u n of d r u g in feed, '
0 .Of11
ILTl\LI\
1 l a lked
I iiactive I tiactive
0.01 2.5
Slight IIarked
0 , 000.23
l l a r hecl
.\fat ked Ilarked
I Ii~igtiificar It Iiisignificaiit Insignificaii t
0 . 01) 1
1I :died
0 .0 I
I tibigriificaiit Insigriificai I t Inhignificant
0.01 0.01
~ h mixt c i i w was dilut,ed wit,h ati eqiial vol of ice-water and stirred overtlight. TK(Jxiich rutis were combined and the product, then \\:is extracted with several portions of CHzCl?. The extract \vas \vx.ihed \ v i t h IlrO arid dried. Removal of the solvent gave :I J - p I l o w oil. Trii iiratioii with petrtaiie followed by soliitioti i i i i-l'rOtl niitl vurefiil diliitioii w i t h pentaiie (with chilling ; t i i d sc*r:itc'hirig)gnvr 114 g of i t whiicl si)lid, nip 68'. The striictiti'e \\a- i ~ i i t i f i r i i i dIiy : t i i a l ) - h i s ntitl tiiiir. Procedure D. 2-CyclopropyImethoxy-5-nitrophenol.----A so111iiiiii o f 40 g o f 2-cyclopropylmethoxy-5-nitrophenyl benzoate, lii0 nil of 05(~';EtOH, aiid 11.5 g of SaOH (pulverized pellets)
\ \ a s refliised for 2 Iir iititler S 2 . The cooled soliiiioii \vah trcatetl with 300 ml of €120 and theii acidified \vith 40 ml of colicelitrated NCl. The prodiic't \\-a> extracted with 400 ml of CI-I?CI?. 'The extract \vas theii stirred for. 2 hr with 500 ml o SaHCOa.The layer5 were separated atid the O I I C P with 100 ml of H 2 0 . The organic lager was anti evaporated, leaving a yellow prodiict (1:3.0 g) mp 104-105°. The prodiict wits essentially pitre as iiidicated h y analysis, nmr, aiid ir. Procedure E. 2-Cyclopropylmethoxy-5-nitrophenylTetradecyl Ether. A hiispeiisioii of 10.0 g (0.048mole) of 2-cydopropylniethosy-~-tiit~i~pheiiol iti !I0 nil of P h l l e was mixed with (0.048 mole) of piilverized S a 0 1 1 pellets. The mixt,iire refl~istemperature for 1 h r . A red salt e reactiott. After removal of the .solvent, i i ~t'ucuo the r e d u e \vas niixed with 90 in1 of I)AJF, 0.25 g of of tetradecyl bromide [tip 17&17io 'The rertction was allowed t o pro20 hr.. The cooled reaction mixture H,O, and the tan precipitate was c product, obtained on removal of ed f r o m a sinall amount of hexane
Procedure F. Diethyl [ ~4-Cyclopropylmethoxy-3-tetradecyloxyanilino)m~thylene]malonate.----A solution of 13.5 g (0.033 niole) of 2-cyclopropylm -
