POTENTIAL ASTIRADIATION AGEVTP
Rfarch 1969
245
MeNCH,CH,NCH,CH,OH
I
-
MeNCH,CH,OH
I
// MeNCH;CH2C1
I Ts
TS MeN(CH,),NH
I Ts
1 Ts
-
Ts
I
Ts 13
MeN(CH,),N(CH,),OC,Hj
I Ts
14
12
MeNCH=CH2
-+
11
10
I
TS
.--t
1 Ts
MeNH(CH2)3NH(CH2)20C,H,Br-p2HBr 16
15
I I
Ts
I
19a, n = 2 b, n = 3 c,n=4
Ts 17
t MeNHTs
-+
MeN(CH,),N
I
20a,n=2 b,n=3 c,n=4
w,
I
Ts 18a,n=2 b,n=3 c, n’4
idinone-ring cleavage. It was, in fact, in the contrast, the action of 48Oj, HBr on the crude 2-acetoxyethyl derivative 17 afforded the desired 19b. The version of the sulfonamide 18a into 19a that a 30% solution of dry HBr in HOAc containing phenol was cleavage of an acetoxy group in conjunction with oxfound to be a more suitable reagent for simultaneous azolidinone-ring cleavage with 30% dry HBr in HOAc detosylation and decarboxylative ring cleavage and to was recently reported.* These examples involving require less vigorous conditions than aqueous 48% the acetoxy blocking group illustrate a means whereby usually troublesome hydroxyethylations of primary HBr. The use of phenol as a bromine scavenger in this type of reaction generally affords cleaner products, amines with ethylene oxide can be circumvented when the end product is to be an N-substituted 2-bromoalthough good results are often obtained without it. Prior to the advent of the oxazolidinone method the ethylamine hydrobromide. synthesis of the intermediate 19a was undertaken by a A reaction sequence based on the conversion of 14 route based on the previous conversion of 1 into 8a into 19b was chosen for the preparation of N-(Zbromo(Scheme I), but proceeded no further than the conethyl)-N’-cyclohexyl-l,3-propanediamine dihydrobroversion of K-(2-hydroxyethyl)-N-methyl-p-toluene- mide (24b), but steric hindrance unexpectedly altered sulfonamide (10) into the 2-chloroethyl derivative 11, the initial steps as indicated in Scheme 111. The preparation of 14 by the addition of p-toluenesulfonyl the attempted condensation of which with 3 produced chloride to S-methyl-l,3-propanediamine S-methyl-N-vinyl-p-toluenesulfonamide(13) instead in DMF is of the desired bis-p-toluenesulfonamide 12. Two represented by eq 1, but the product formed by a schemes for the synthesis of 19b, one of which was 2CHaNH(CHz)3SHz + 2 T s C l - j successful but was later superseded, were based on the 14 + CH3NH(CH2)3NH2.2HCI ( I ) substitution of N-methyl-N,S’-trimethylenebis-p-toluenesulfonamide (14) by a group that would cleave similar treatment of N-cyclohexyl-1,3-propanediamine during subsequent detosylation. The protracted action was the HzO-soluble hydrochloride of N-(S-cycloof refluxing 48y0 HBr on the 2-phenoxyethyl derivative hexylaminopropy1)-p-toluenesulfonamide (21), which 15 apparently achieved both detosylation and ether precipitated as the free base at pH 9 and whose struccleavage, but the purple amorphous product could ture was attested by high solubility in a strongly not be decolorized and recrystallized. The action of alkaline solution. I n the alternative synthesis of 24b 3OY0 dry HBr in HOAc on 15 effected detosylation, and the lower homolog 24a from the sulfonamides 23, but not ether cleavage, and resulted in the isolation of steric hindrance was evidenced by the requirement of a ring-brominated product, probably N-(2-p-bromomore vigorous conditions for the alkylation of n‘-cyclophenoxyethyl)-N‘-methyl-l,3-propanediamine dihyhexyl-p-toluenesulfonamide with the 3- (a-chloroalliyl) drobromide (16). That forcible cleavage of 16 with 4byo HBr would produce an effect like that observed (8) J . R. Piper, C . R. St,rinefPllow, .IT.,and T.1’. .Johnston, ,I. firteToC?/d. with 15 was indicated in a trial experiment. I n conChem., 4, 208 (1067).
2 I.(i
I
I
0
0 OcNHTs 26
+
OcX(CHJ,,NKO
u
I
Ts
27a, n = 2
b.n=3
OcKH2
--
OcNHCH,CH,N
\
OcNH(CH2),NHCHLCH2Br.2HBr 29a. n = 2 b. n = 3
-
OcNH(CH2j,NHCH2CH,SY 30a. n = ": Y = PO,H, b. ii = 31 Y = SO,H c. n = 3; Y = P0,H2 U
I
u
28
'I-ox:Lzolidinone\ 6a, b; the alkylations were effected :it 130-1-10" in dimethylacetaniide ( D l l h C ) after an attempted alkylation with 6a at 115" in D l I F had fitiled. In marked contrast to the methyl and ethyl :malog.;, 24b gave a crystalline Runte salt (25) hydrohromide (although in low yield) when treated with equimolar amounts of Sa2S20J and XaOAc. The preferred pro(-edure, however, involved neutralization of the reaction mixture with YaHCOd, which allowed t h e isolation of 25 as a crystalline hemihydrate in high yield. On the other hand, the dibplacement reaction of 24b with trisodium phosphorothioate in H2O-DlIF :it room temperature was incomplete after 2 days. 'I'hc 9(2-hromoethyl)-N'-oct yl-a, w-alkanediamine cli1iydro~)romides29 were prepared from the oily, tiiioharac~terizedsulfonamides 27 and converted into t h e corresponding phosphorothioates 30a, c and thc t hiowlfate 30b as outlined in Scheme IT. In a variation of this sequence, the preparation of' S-octyl-p-toluenehulfonamide (26) was by-pawed by the direct alkylation of octylamine with 6a to give crude 3-(?-octyIaminoc.t hyl)-2-oxazolidinone (28). Trilithium phosphorotkiioate \vab the reagent uqed in the preparation of 30a, C : thc isolation of 30b was effected by XaHCO3 ~~eutralization as in the preparation of 25. The use of trilithiiim rather than trisodium phosphorothioate yometimes facilitates the isolation of crystalline derivatives as wau the ( m e with 20c. Severd approaches to the hynthezi5 of the h--(?I~ronioetl.iylj-~'-~~heilyl-a,~-al~:~riedianiiiie dihydrobrotnideh 38b, C, from which thtl respective thionilfntr39a, b c w dcrivcd, :w de1iiic:tted i n S c l i c r n ~V. Tho
corivenience of the squeiice beginning with the rcduction of :3-:~iiiliriopropionitrile (31j n a- liniittd by the troublesome separation of '-(3-:inilinopropylan1ino)ethanol (33) from the mixture of produvts i hat resulted from the treatment of S-phenyl-l,3-propancdiamine (32) with ethylene oxide. In the search for a n alterriative route. 32 was cwnvcrted into the bisp-toluenesulfotianiide 34. from which both the 2phenoxyethyl and hcetoxyethyl derivatives 35 ant1 36 were derived as (wide oils, but neither caould bc converted into ibolable 38c by treatment with 4hL/( HBr. The route oia 33 eventually outmoded by the hydrogen bromide cleavage of t h e S - W - ( ~ - O S O - : ~ oxazolidinyl)alliyl-p-toluenesulfo~iariilider (37). II initial c.leavage of 37a with SO%, dry HBr iii HOLici i i t h e presence of slightly inore than an eyuiinolur aniouiit of phenol and with a finishing reflux period. however. resulted in tht. iiolittioii of an ana1ytic:tlly pure ringbrominated product, probably S-(2-bronioethyl)-N'(p-bromophenyl)ethylenediamine dihydrobroinide (38a). King bromination was avoided by a threefold increase iri the amount of phenol used and elimination of the reflux period. The treatment of 38c with equiniolar amouritof Xa2SnO3arid S a O h c in H20 at 90" gave the Buntc. yalt 39b, but t h e qame treatment of 38b resulted in i h r precipitation of elemental S and the evolution of SOL. Several procdural variations designed to avoid t hc effects of acidity on S a A O a gave similar results, iticluding the prior partial neutralization of 38b with :in equimolar amount of SaHC03. The forniation of 1phci~ylpiperazinrin the 1at tcr variation as indicatrt-l iti Schcmc I' W:L- dcnioriztr:iCcd t)y the i5ol:ition of thcl
.\ Tnrrh 19GO
247
POTEKTIAL ANTIHADL4TION AGEXTS SCHEME
C,H NHCH-CH-CA 31
-+
/
C,H NH(CH.),NH-
v C,H NH(CH 1 SHCH CH-OH
-+
32
33 I
C6H5N(CHZ)JH + C
I
Ts 34
t
Ts
.1 I
Ts
V
I
Ts
38a, Z=Br; n = 2 b, Z= H; n = 2 c,Z=H;n=3 1
/
36
T S
39a,n=2 b, n = 3
37a, n = 2 b, n = 3 38b
NaOAc Or
NaHCO
[C,II-NnNH.HBI]
‘a SO, +
S
+
2NaBr
+
C,H,N n NH
W
W
-
C,HiN n NTs
U 40
w
SCHEME VI
-
EtOJ -+HTs
E ~ O , C - - @ ~ ~ H J , ,0 N
U T S
41
42a, n = 2
b,n=3
39b
+
38c
+-
sulfonamide 40 following treatment of the reaction spectral evidence and Br- analysis, the identity of the mixture with NaHCOs and p-toluenesulfonyl chloride. product was rationalized as the 3-bromobenzoate hyThe preparation of 39a mas ultimately effected by the drobromide 43a. The problem of ring bromination slow addition of powdered 38b to a warm solution of an in the preparation of the benzoate dihydrobromide equivalent amount of Na2S203 and 2 molar equiv of 43b was subsequently overcome by doubling the molar NaOAc in H,O containing DMAC as a catalyst. Satratio of phenol. Stoichiometric differences in the isfactory procedures for the conversion of 38b, c into conversions of the monohydrobromide 43a and the the corresponding phosphorothioates were not devised. dihydrobromides 43b, c permitted the preparation of The synthetic sequence shown in Scheme VI was the thiosulfate 44a in the absence of SaOAc as buffer. followed in the preparation of the p-aminobenzoic acid An initial effort to hydrolyze 43c to p-[3-(2-bromoderivatives 44. Forcible conditions were also requisite ethy1amino)propylaminolbenzoic acid dihydrobromide to the conversion of ethyl p-(p-toluenesu1fonamido)(45) in refluxing 48y0 HBr resulted in decarboxylation, benzoate (41) into the ethyl p - IN- [~-(~-0x0-3-0x- the product being identical with the previously preazolidinyl) alkyl 1-p-toluenesulfonamido1 benzoates 42. pared 38c. Hydrolysis without appreciable decarboxCompletion of the sequence leading to the thiosulfate ylation was achieved on a pilot scale by refluxing a so44c was routine, but benzene-ring bromination was lution of 43c in 10% HBr, but decarboxylation also again encountered in the hydrogen bromide cleavage occurred in a subsequent scale-up because of an inof 42a in HOAc in the presence of an equimolar amount advertent increase in reflux time but was not recognized of phenol as bromine sravenger. On the basis of until the derived Bunte salt was identified as 39b.
249
PHWPHOROTHIO wcs A N D I ~ LUL L D COMPOC:RDP IINH(CHL),~'HCHICHISY Approx
It
Et
LD,a, m d k e
11
>200
2
150 r -
i%I
Et
2
830
400 200
Et
3
330
c-
Et
3
JI(3
2
JI?
3
750
POa&(. 2.5IISO)
900
b0O
Me
4
24 0
Cy clohexyl
3
250
43
37.5 500 250 125 400 400 200 4 00 200 100 50 180 90 150 150 m-
ID
a
Vehicle of adrnin
Drug dose, mg/kyc
75 30
Water Water Water Water Water Water Water Water Saline"
PBf PI3 PI3 PB
PU PB PB C3iC-TW ChlC-Tw PB CXC-Tw PB
CMC-Tw
pH ol prew
5.7 3 .7
6.4 6.4 6.1 6.1 6.6 6.6 6.6 6.9 ti . !I ti .!I 7.0 7.0 7.5 i.3 7.5 7.5 6.5 8. 3 6 ,5 8.5 6.1 6.1 8.1 6.6 6.6 6.4 6.4 6.6 6.6
3U-dlt)
burvival. L / O ~
0 0 13 0 0 0 100 100 7 73 47 20 100 Si 46
13 33 0 0 0 0 0 0 0 urecontaining precipitated 30c as a semisolid. EtOH (100 ml) was also added, and continued stirring led t,o complete solidificst,ion of the precipitate. The solid was collected, washed (EtOH, 30-60' ligroin), and air dried (see Table 111).
Acknowledgments.-The authors are iridebkd to Dr. D. P. Jacobus for antiradiation d a h , to Dr. Jacobus arid Dr. T. R. Sn-eeney for their interest arid encouragement, and to Dr. W. J . Barrett and members of t,he Analyt'ical and Physical Chemistry Division of Southern Research Inst'itute for microanalytical and spectral determinations.
Synthesis of Potential A n tiradiation Agents from 3- Substituted 2-Oxazolitlinones Derived from Phenol, Benzenethiol, and Related Compounds' ROBERTD. ELLIOTTASD THOMAS P. JOHKSTON Ketteriny-Jleyer Laboratory, Southern Research Instilzrte, Birmingham, Alabama 35,805 Received August 5 , 1068 The IIBr cleavage of h u b s t i t iited 2-uxazolidinoncs was effectively :ipplied i l l the byntlicsis of h'-substituted and N,S-disubstituted derivatives of 2-aminoethanethiol in which the ?; substituent is a 2-phenoxy-, (phenylthio)-, (phenylsulfonyl)-, or (2-pyridy1thio)ethyl or a correspondingly 3-substituted propyl group. h'one of these modifications of the amino group led to radioprotective activity approaching that of the parent compounds. Bmong the thiols, disulfides, t,hiosulfates, and phosphorothioates prepared, the fallowing were slightly radioprotective in mice: sodium S-2-(2-phenoxyethylamino)ethylhydrogen phosphorothioate (4c), S-2-[2-(phenylthio)ethylaminolethyl hydrogen thiosulfate (4g), S-Z-[3-(phenylthio)propylamino]ethylhydrogen thiosulfate (4j), N,N '-(dithiodiethy1ene)bis [3-(phenylthio)propylamine] dihydrochloride (5c), and lithium S-2- [a-(phenylsulfony1)propylaminolethyl hydrogen phosphorothioate (1Oc). N,N'-(Sulfonyldiethylene)bis(S-2-aminoet~hylhydrogen thiosulfate) ('lb), which was prepared by an aziridine ring-opening reaction, showed fair radioprotection.
The general utility of the hydrogen bromide cleavage of 3-subst~ituted 2-oxazolidinones in the synthesis of uniquely substituted S-('Abromoethyl)amines has been described in a preliminary communication,2 and its subsequent application in the synthesis of potentially radioprotective derivat'ives of 2-aminoethanethiol (thiols, thiosulfates, and phosphorothioates), in which the K substituent is some type of aminoalkyl group, has recently been r e p ~ r t e d . ~This paper describes t'he introduction of other types of substituents through the use of nucleophiles other than amines and amine derivatives in the preparation of suitable 2-oxazolidinone intermediates. The 3-substituted 2-oxazolidinones 2, which were derived by the alkylation of phenol and benzenethiol with the conimerically available 3-(w-chloroalkyl)-2oxazolidiriories 1, proved to be suit'able starting points
1
Cl(CH2)nN
0
U la,n=2
b,n=3 ( 1 ) This investigation was supported by the U. S.Army Medical Research and Development Command under Contract No. Dh-49-193-RID-2028. ( 2 ) J. R . Piper, R . D . Elliott. C. R. Stringfellow, .Jr., and T . P. Johnston, CAPm. I n d . (London), 2010 (1966). ( 3 ) (a) J. R . Piper and T. P. Julinuton, J . Ory. Chem.. 33, 636 (1968); (1,) J. R . Piper, C. K . Stringfellow. Jr., R . D. Elliott, and T. P. Johnston, J. M e d . Cliem., 12, 236 (196Y); ( e ) J. R . Piper, C. K. Stringfellow, Jr.. and T. P. Johnutun, ibid., 12, 244 ( l Y t j Y ) .
for the co1iversions depicted in Scheme I. The hydrogen chloride cleavage of 2c in refluxing 1-propanol4 in an initial experiment was eventually superseded by the milder, more convenient and productive hydrogen bromide cleavage in AcOH. The halides 3~ and 3d afforded the same thiosulfate, 4g, but, apparently because of the reaction rate difference between 3c and 3d, a phosphorothioate could not be derived from 3c, the required longer reaction time allowing extensive decomposition of the reagent Sa3PS03. Attempted purifications of the impure, hygroscopic sodium hydrogen phosphorothioates derived from 3d and 3e succeeded only in the case of 4k, but the reaction of 3d with the more soluble Li3PS03proceeded smoothly in aqueous DRIF and produced the hydrated crystalline Li salt 4h. Three methods for the synthesis of S-substituted S-Zaminoethyl hydrogen thiosulfates in which the S substituent is an w-(alkylsulfony1)alkyl or w-(arylsulfony1)alkyl group were described recently.5 Another method, which is shown in Scheme 11, has been demonstrated by the preparation of Y,N'-(sulfonyldiethylene)bis(S-2-aminoethyl hydrogen thiosulfate) (7b) by ring opening of the bisaziridine 6 with Sa2S,03 and A C O H . ~The generality of this method, however, is H. Arnold and H . Reckel, Arzrieim.-Forsch., 14, 750 (1964). ( 5 ) 0. L. Salerni, R . N. Clark, and B. E. Smart, J . Chem. Soc., 645 (1966). (6) Cf. F. C. Schaefer, J. T. Geoghegan. and D . W. Kaiser, J . Amer. Chem. Suc., 7'7, 5Y18 (1955);J. R . Piper, C. R . Stringfellow, Jr., and T . P. Johnston, .I. .lfed. Chem., 9 , 911 (1966). (4)
