MOFFETTA N D PICKERINC
1100 Journal of Medicinal Chemistry, 1971, Vol. 14, -Vo. I1
l,l-Diphenyl-2-methy1-3-( 1-pyrrodidiny1)propane.HCI (169). --To a suspension of 29.5 g (0.1 mole) of 15 i n 600 ml of liq X€13anti 13.4 ml of Et011 was slowly added during 2.5 hr 6.92 g (0.3 g-atom) of N a (spheres). The mist was then stirred for ail add1 1.5 h r and allowed t o evap overnight. Ice watrr w:is added atid the mixt was cstd with 13t20. The 1st 2 0 s(111iW:L.S washed ( 1 1 2 0 , satd NaCl) aiid dried (NanSO4). I~ilttiaiid relnoviil of the solvent gave 28.2 g of nearly colorless oil. This was dissolved i n 2.50 ml of hexane arid chromatogd o i l n c v ) l u m i i of I kg of neutral i\IzO3 (W(ielti~) iirid eluted with 1-1. portions of hexaiic coritg increasing amounts of abs ISt20. The 1)ulk of t h e product came off with solvent coritg 27; Et2() giving 15.4 g of oil. This
was dissolved in Et& and acidified with ethanolic HCI, yielding 18.83 g (,57%,)of white solid, mp 214.5-217”. The same cornpd (169) was obtained i n poor yield t)y treating 16 with SOCI,, removiiig the solvent, and hydrogenating the resulting c:rude :~-chloro-3,3-diphe11yl-2-methylpl:opyl-~-pyrrolidine.IlC1 i n the presence of Pd’C. .Ins/. (CzoIi26ClN) C, 11,
(I,N.
Acknowledgments.-Thc authors \\.ish to thank our l’hysical and Analytical khrmistry Unit for analytical iind spectral data, 3Ir. 11. I;. Tripp for technical assistance, and Ilr. R. V. Hcinzclman for guidance.
Central Nervous System Agents. 2. Synthesis of Diphenyl Primary and Secondary Aminopropanols I l O B E l i T B R U C E R ~ O F F E ? ’ r * ANI) T I M O T H Y
1,.
I’ICKERING
liesearch Laboratories, The C‘pjohn Conipany, Kalnmaroo, .IIichzgan Received .\larch 12, 1Y?1
A series of 1,1-diaryl-2-r~iethyl-:~-[ (primary aiid sccotida~~)nmirio]prc~paiiols (I, 11 and ’or I t ’ = €1) were pre1):~rcdfor‘ testing as CNY agents (atiticotivulsatils, anorexigenic-;, and their efTec*1on simple i:eflexcs). The primary amines were prepared by reduction of the correspoiidiiig nitriles arid most of the secoiidary amines by reductive alkylation of the primary amities. A new cleavage of &arnino esters by Grignard reagents is d ~ scribed. The primary amine (l,l-dipheiiyl-’-methyl-:~-~~iiiiopropalio~) was resolved into its optical isomers and thc 1 isomer was tested in man.
The intcresting CXS stimulating cff cxcts accompanied by low anticholinergic sido efftbcts found for tliv tertiary amines‘ (I) havc encouraged us t o cxpand tho saritrs t o 0 1 1 CIII (CaH5)*L-CII(:H2~l1 I 1’1
I
I
includo primary and secondary amincs (I, I1 and/or II ) . Thew could not be satisfactorily prrparcd by thc mcthods usrd for thcl tcrtiarj- aminw. Althougli somc workers2 havc succwsfully prcymred similar primary or secondary amino alcohols by thc: Grignard rvaction on @-aminotstrrs or @-aminoketonw, wc found thew methods unsatisfactory for our compounds. W h c ~ imcxtliyl @-(isopropy1amino)isobutyratcl or @-(alIyl:imirio)isobutyr~t(,i v ( w added to PhlIgHr or I’hI,i undrr wilditions that Jvorlicd ~ ~ with 1 tortiary 1 amino est(irsl rion(~of thc dcsirrd amino alcohols wcrv isolatcd but iristvad about a 50yo yield of N-isopropyl-or N-allylb(~nzy1amincwas obtaincd. This might hr formuI a t d :H ;I rworsv condmsation rcwtion arid explained by clwvagc of thci :inion formod by initial abstraction of t h v proton from 3, followid by addition of mort’ 1’hAIgBr to the formal compouiid. Of coursc, PhlIgBr may also add t o the. tistcr prior to, simultancwusly with, or subscqurnt to th(\ clcavap. This now1 rc,action may provt’ usvful for the preparation of bcnzylamincs from aromatic Grignard roagents. When t h r Grignard reaction was carricd out at -20’ as suggostcd by Adamson2a :i small yield of thc dcsircd N-isopropylitmino alcohol 28 \vas obt aint.d. Howcvcr, ( 1 ) Article I : I < . 13. h l u f l c t t , R . 1.;. Stnilie. and I , . I.. Skalelrk?, J . M e d . Cirem., 14, 1088 (1971). ( 2 ) ( a ) 1). IV. Adamson. J. Clirm. S O C . , S u p p l . . 1, S144 (1049): (1)) K. Takaei, Y. Iiasiiya, anti li. liottori, Yakugnku Znsski. 71, 1592 (10.52): ChPm. A b . d r . , 47, 9:312h ( 1 9 5 3 ) : (r) 11, S. 3Ioslier. .\I. 13. Frankel. and 31. Greuory, J . A m e r . Chem. Soc.. 76, 5320 ( l ! j 5 : % ) : ( i l l . I . I.:n+xlish a n d A . I ) . l%liss, i b i d . , 7 8 , 4057 ( I M f i I .
Joumal of Medicinal Chemistry, 1971, V O ~14, . No. 11 1101
CNS AGENTS. 2
A variety of secondary amines were prepared from the primary amine 1 by either of the two methods indicated.
ClCOR
The N-methyl compounds 17 and 19 were prepared by hydrogenolysis of the corresponding N-benzyl-Nmethylamines. The primary amine 1 proved to have very interesting CNS stimulating properties in animals4 and was therefore resolved into its d and 1 forms. This was accomplished by crystallizing its d-tartrate salt to furnish the 1 isomer and its I-tartrate salt to give the d isomer. The levo rotating isomer (6) proved t o be the more potent although the d isomer (9) also had interesting properties, being half as active on some parameters but only 0.2 as active on other^.^ The I isomer (6) was sent to the clinic for testing in humans afflicted with various mental diseases. However, undesirable side effects were encountered which may limit its use as an antidepressant.
Experimental Section6 l,l-Diphenyl-2-methyI-3-aminopropanol(l).-To
a mixt of
113.5 g (2.91 moles) of NaNHzeand 1.75 1. of abs EtzOwas slowly added wit,h stirring a soln of 300 g (2.75 moles) of Ph2C0 and 330 ml (6 moles) of EtCN in 2 1. of abs Et,O. After refluxing for 3 hr and standing overnight the mixt was poured into 6 1. of ice water.
The aq soln was extd with EtzO and the EtsO solns were washed (HkO, dil HCl, H20, satd NaC1) and dried (Na2S04). After filtn, the Et20 soln of the crude nitrile was concd to 4 1. and slowly added with vigorous stirring t o 343 g (9 moles) of LAH and 500 ml of abs EtzO. The Et20 gently refluxed during the 3.5 hr which was required for the addn. The mixt was then stirred under reflux overnight and cooled wit,h an ice bath. To the reaction mixt was carefully added dropwise 360 ml of HzO and then 54 g of NaOH in 1.5 1. of H20. After thorough mixing, the mixt was filtd and the solid was well extd with Et,O. The Et20 filtrates were extd with several portions of dil HCl and t,he acid exts were washed (Et20). The aq solns were basified with cold dil NaOH and the cryst free base was collected, washed (HzO), and dried, giving 313 g of white crystals, mp 122.5-124.5'. (4) The pharmacology of these compounds is reported in article 3 of this series, H. H. Keasling and R . B. M o f f e t t , J .M e d . Chem., 14, 1106 (1971). ( 5 ) Mps were taken in capillary tubes with a partial immersion thermometer. Calibration of the app against standard compds showed no need for correction. Absorption peaks of spectra (ir and in selected cases nmr on a Varian A-60 instrument) mere as expected. Where anal. are indicated only by symbols of the elements, anal. results obtained for these elements were within 3 ~ 0 . 4 %of the theor values. (6) Free-flowing powder from Farchan Research Laboratories, Wickliffe, Ohio.
This was recrystd from 1.7 1. of i-PrOH, yielding 266.7 g of white crystals, mp 125-126.5'. Hydrochloride 2.-An i-PrOH s o h of 20 g (0.083 mole) of the base (1)was acidified with a slight excess of ethanolic HCl. Diln of the soln with abs Et20 gave 17.5 g of white crystals, mp 213" dec. Maleate 3.-A warm s o h of 1.2 g (0.01 mole) of maleic acid in 10 ml of EtCOMe was added t o a warm soln of 2.4 g (0.01 mole) of the base 1 in 15 ml of the same solvent. The maleate salt crystd almost immediately, giving 3.5 g of white crystals, mp 179-181.5'. Alternate Method7 for l,l-Diphenyl-2-methyI-3-aminopropanol (l).-A soln of 6.232 kg (26.2 moles) of 2-(~~-benzhydrol)propionitriles in 28 1. of 95% EtOH and 3.85 1. of NHlOH (29y,NHI) was hydrogenated in a 120-1. autoclave with 1.5 1. of Raney Ni a t 75" and 70.3 kg/cm2. The hydrogenation was complete in about 30 min. The product was washed from the autoclave with Et>OH and CH2C12, filtd, and concd under reduced pressure. The residual oil was dissolved in PhH and extd with dil HC1. The aq soln was washed (Et2O) and basified with cold dil NaOH giving 6.04 kg of crude base. This was recrystd from 40 1. of i-PrOH, yielding 5.135 kg (817,) of white crystals, mp 124.5-126.5'. I-l,l-Diphenyl-2-methyl-3-aminopropanol&Tartrate (4).-A mixt of 326.4 g (1.35 moles) of the base 1 and 202.5 g (1.35 moles) of d-tartaric acid was recrystd first from 6 1. of 85% (by vol) of aq LlesCO and then from 2.5 1. of H 2 0 giving 169 g of white crystals, mp 154-188" dec. A sample dried a t 60" (0.1 mm) was found by Karl Fischer anal. t o cont, 0.6 mole of water, [ c Y ] ~ ~ D - 19 ZIC 1" in HzO ( a -0.352 f 0.02", c, 0.9368 g/100 ml, I = 2). I-l,l-Dipheny1-2-methyl-3-aminopropanol (5).-The above 1 base d-tartrate (4) was dissolved in warm H,O and basified with NaOH. The cryst solid was collected, dried, and recrystd from 600 ml of i-PrOH, yielding 86.5 g of 1 base, mp 148-149.5", ( c Y ] ~ ~ D -15.8". A sample recrystd from i-PrOH had mp 148.5-GO", [ c Y ] ~-18.5' ~D f 1" in MeOH (CY -0.305, c, 0.8204 g/100 ml, 1 = 2). l-l,l-Diphenyl-2-methyl-3-aminopropanol~HCI (6).-The 1 base ( 5 ) was dissolved by warming in 240 ml of i-PrOH contg a slight excess of ethanolic HC1. On cooling cryst hydrochloride sepd giving 85.8 g of white crystals, mp 193-196", resolidified a t about 197", and remelted a t 205-215", [ a I z 7 D -41.6 f 1' in HzO (CY -0.75, c, 0.902 g/100 ml, 1 = 2); [ ~ ] Z ? D -38.25 =t1" in N e OH ( a 0.65, c, 0.860 g/100 ml, 1 = 2). By reworking various filtrates, a small add1 yield of pure 6 was obtained. The total overall yield for the resoln was 517, of the theoretical yield (one-half of the starting [dl]material). d-l,l-Diphenyl-2-methyl-3-aminopropanol&Tartrate (7)The filtrates from the prepn of the above 1 base d-tartrate (4)were evapd t o dryness and all fractions having rotation [ a ] D +23' t o +29' were combined (about 300 g). This was dissolved in H20 and basified with NaOH. The solid base was collected, washed well (HzO), and dissolved in 3 1. of hot 85% aq MezCO contg a slight, excess of 1-tartaric acid. On cooling, crude d base l-tartrate crystd and was recrystd from 1.7 1. of H20, yielding 192.2 g of white crystals, mp 152-158'. A sample was dried at 40" (0.1 mm), [ c Y ] ~+19.0 ~D - 1' in Hz0 (CY = +0.342", c, 0.881 g/100 ml, 1 = 2). Karl Fischer anal. indicated only 0.38Yc HzO. S n a l . ( C Z ~ H Z ~ NCalcd: O~) C, 61.37; H, 6.44; N, 3.58. Found: C, 59.87; H, 6.93; N, 3.55. d-l,l-Diphenyl-2-methyl-3-aminopropanol @).-The above d base I-tartrate (7) was dissolved in warm H20 and basified with NaOH, the cryst solid was collected, dried, and recrystd from 800 ml of i-PrOH, yielding 104.1 g of d base, mp 148-149.5", [ @ I D +17.7 f 1" in NeOH (CY +0.340", c, 0.9606 g/100 ml, 1 = 2). d-l,l-Diphenyl-2-methyl-3-aminopropanol~ HCI (9).-A soh of 10.2 g of the d base 8 in 63 ml of warm i-PrOH was acidified with ethanolic HC1 giving 8.7 g oi white crystals, mp 191-192", resolidified, and remelted at 205-210", +42.2 f 1' in HsO ( a +0.70", c, 0.8216 g/100 ml. I = 2); [ a ] z 5 +38.45 ~ f 1" in MeOH (CY +0.64X0, c, 0.8426 g/100 ml, I = 2). l,l-Diphenyl-3-aminobutanoP(10).--4 s o h of 310 ml (1.53 moles) of 3 M PhlIgBr was cooled t o -20" and a s o h of 2.5 g (0.19 mole) of ethyl 3-aminobutyrate in 100 ml of abs Et20 was slowly added with stirring at, -20". The mixt was stirred at -20" for 2 hr, then at 0" for 2 hr, and poured into ice water cont'g a slight excess of HBr. The aq lager (contg a little gummy hydro(7) This method was developed by Mr, Melvin A . Rebenstorf of our high pressure laboratory. (8) H. Lettre and Ii. Wick, Justus Liebigs A n n . Chem., 603, 189 (1957). (9) A. T . Austin and J. Howard [ J . Chem. Soc., 3278 (1961)l report (without details) an optically active (+) isomer of this compound.
1102 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
MOFFETT A N D PICKERING
"?
N
32
3
3
0
2
N
b
"
N
Q: I
Q,
3
.t
X CD
0 N
m
2 N
Q,
LA
2
i
c.l
Joumal of Medicinal Chemistry, 1971, Vol. 14, No. 11 1103
CNSAQENTS. 2
x-
x-
x-
x-
u'
u'
d
u'
ad
3
00
3 00
*
I-
E 0
-4-
1104 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
MOFFETTAND PICKERING bromide) was washed (EtzO) and basified with NaOH. The mixt was well extd with Et20 and the exts were washed (HzO, sat NaCl) and dried (XaSS04). Filtii and evapn of the solvent in vacuo gave gummy solid which was crystd t>wicefrom 2'-PrOIT, yielding 1.47 g of cryst solid, mp 156.5-157.,5". 2-(a-Benzhydrol)-3-methylbutyronit.rile (62).-To 20.17 g i0..53 mole) of NaSHZ6in 200 ml of aha Et20 was slowly added with stirring a eo111of 91.0 g (0.5 mole) of Ph&O arid '30.5 g (1.09 tnoles) of isovaleriiiiitrile i n 300 ml o f ahs Et20. After stirring under reflux for 3 hr, the mixt was cooled and poured into ice water. The aq layer was extd with Et20 and the Et& solns were washed (H20, dil HC1, ITSO, satd NaCl). After drying (NaISOI) and filt,g, the Et20 was evapd giving 134 g of crude nitrile. This was td from 400 ml of PhH, yielding 66.7 g (.jOG;() of white r r Is, mp 167-169". . 4 n d (C18HlgNO)(1, € I , ?;. l,l-Diphenyl-2-methyI-3-(methylamino)propanol(17).--A ~~1111 of X4..i g (0.1 mole) ( i f I, l-dipheiiy1-2-methyl-3-(.~-beiizyl. . \ ~ - m r t h ~ ~ 1 a m i i i o ) p r o pi iai l200 ~ ml of JIeOH was hydrogetiated with 2 g of 10$; Pd/C at i3.5 kg/cmz aiid room temp. T h r theoretical amt of 112 was alisorbed iii 3 hr. Filtn and evapii in mciio gave white cryst solid which was recrystd from 125 nil of i-PrOH, yielditig 20.7 g of white crystals, nip 112-114'. S-(3,3-Diphenyl-3-hydroxy-2-methylpropyl)acetamide (21).-A so111of 30.3 g (0.12 mole) of 1 in 1.2 I . of EtzO was added with dirritig t o a mixt of 10.2 g (0.13 mole) of pyridine and 13.3 g (0.13 mole) of .4c20 i t i 100 nil of EtrO. After refliixiiig for 2 hr the mixt waq p o i i r t d iiito i c , e w:iter. T wtl\ict reniaiiied itisol iii both layers yieldiiig s'3:< ~s i i f a h i t e alL, nip 15S--l59'. Recrystil from i-PrOH did 1101 m i k e the 1,1-Diphenyl-2-methyl-3-(ethylamino)propanol (22).--A sol^^ of 24 g (0.12 molc) of amide 21 i i i 300 ml of TFIF was slowly added tvith btirriiig 1 o 9 . 1 g 10.24 mole) of 1 A I - l i n 100 In1 Of T H F . After refliixiiig overnight most of the solvent was distd aiid replaced by EtrO. There was theti slowlj- d d e d in succession 9.1 nil of ITLO, 9.1 rnl i l l 20f'; NaOT1, arid 27.3 ml more of H.0. The mist was filttl alii1 t h e solids were well estd with Et&. The I.:t,O s o h i s werr e s t d with dil ITC1 and the hasifieti with iTaOlr, The free hase was rec yirldiiig 1S.3 g of white solid, mp 103-104°. l,l-Diphenyl-2-methyI-3-(propylamino)propanolMaleate (25).--A 0.1-g sample of PtO, i l l 50 in1 of EtOH was hydrogeiiated i o Pt. Theii w i . r :idtied 24.1 g (0.1 ino EtOFT aiid 6.4 g (0.1 mole) i l f J:tCFTO. 'I' :it :3.,5 kg/vm2 atid r o o m temp. Xl)oiit 75( 112 was atisorlied i i i 5 hr 11). whirti t if iiearly colorless oil. c and a solit i i f 11 .(i g d. Thi-. soln was dild t i ] turbidity with Et,O atid o i i standing crystals sepd, yieldi white solid, nip 110-1:l5". By repeated frnctioiral ( IStOAc the tiesired prcidiic.1 W I S sepd f r o m the 1 the startitig nniitio 3, yirldiiig 17.:3 g of white 14G . .Oi, c1-[2-(Isopropylideneamino)-l-methylethyl] benzhydrol (26): A s o l i i of 12.1 g (0.03 molr) of 1 was dissolved i n 75 nil of SIe2C0 at the 1111. The solii wax filtd aiid c o i r c d hy boilitig t o SO nil, givitig, on cooling, 11.1 g o f white crystals, mp 135~5-137.5'. l,l-Diphenyl-2-methyl-3-(isopropylamino)propanol (27).--A I I of 24.1 g (0.1 mole) of 1, ,'36.8 ml (0..i mole) of AIe2C0, arid 7 mi iO..i mole) of AcOIT i n 75 ml of EtOIT was hydrogeiiated h 1 g of PtO, at 3.5 kg/crriZ and room temp. The theoret.ica1 amt of FTr was absorbed it] 5 miii. The so111was filtd, evapd, dissolved in dil IICI, and \rnshed (Et20'l. T h e aq s o h was basified Tvith Sa011 aiid rstd with E t 2 0 . Afler washing ( 1 1 2 0 , satd ying (Kin,S04) the EtzO removed giving 2q.4 g tals, rnp 05-99.5'. Re t n from i-PrOH raised ley S i was successfully the tnp t o 101-102". 111niiother riiii iised (withoiit AcO1-I) i t 1 place of the PtOt. P h M g B r on Methyl p-(1sopropylamino)isobutyrate.--To 1 1. i:3 moles) of ethereal :3 JI PhSIgBr in 1.2 1. of T H F was added 79..5 g (0..5 niolei of methyl p-(isopropylamiiio)i~ob~it~~ratelO in S O 0 ml i i f TIIF. A f t cr rrfliixiiig for 3..5 hr ahoiit two-thirds of the ~rilventaa. diGtd, :tiid the residiie was poured into ice water col1t.g a slight exce,w of I113r. The :iq aolii was washed (EttO) atid basified with S a O H . The ~iisprnsionof SIg(OH)2was well estd wit'h Et,O which was washed ilIiO, satd XaC1) arid dried (?l'asSO,). After filtn and evapri of the wlvent, 70 g of crude liqnid free 1
~~
110) R . c'. Smith and P. 11. I3inkley. J . Org. Chem., 24, 240 (1959).
J o u d of Medicinal Chemistry, 1971, V O ~14, . No. 11 1105
CNS AGENTS. 2 base was obtd. This was dissolved in 200 ml of hexane and after standihg in the refrigerator was filtd from a small amount of cryst solid to unknown structure, mp 139-141". The hexane filtrate was evapd to dryness i n vacuo, the residual oil was dissolved in Et20 and acidified with ethanolic HCI. The resulting hydrochloride was collected, washed (EkO), and dried, giving 66.7 g of crude hydrochloride, mp 167-172'. This was recrystd from i-PrOH, yielding 40.4 g (43.6%) of salt, mp 192-193". Recrystn from abs EtOH gave 27.5 g of crystals, mp 192-194". This was found by ir, nmr, anal., and mmp with an authentic sample to be N-benzylisopropylamine .HCI. 11 Another run, using 0.6 mole of PhMgBr and 0.2 mole of methyl 8-(isopropy1amino)isobutyrate in E g o , was stirred below - 20" for 2 hr and below 0" for an additional 2 hr. I t was decompd with ice and aq NHICl giving 3 layers. The oily middle layer was strongly acidified with aq HBr and washed (EtqO). Crystals sepd giving 13.13 g of solid, mp 169-174'. This was recrystd first from i-PrOH and then from H20, yielding 6.66 g (9.3%) of white crystals, mp 186-188'. This was identical with the hydrobromide 28 (Table I). A run using PhLi in place of PhMgBr a t 0" to 5 " gave as the only product isolated a 5OTc yield of N-benzylisopropylamine. HCI. N-Benzylisopropylamine .HBr (63).-An E t 2 0 s o h of 5 g (0.033 mole) of IV-benzylisopropylamine was acidified with 4XYc aq HBr giving 5.6 g (72v/o) of the salt, mp 213-21.5". This was recrystd from i-PrOH, yielding 4.6 g of white crystals, mp 214216'. Anal. (ClaH16BrN) C, H, Br. PhMgBr on Methyl 8- (Ally1amino)isobutyrate.-In a similar way 39.2 g (0.25 mole) of methyl p-(allylamino)isobiityratelz and PhMgBr were allowed t o react in Et20 a t reflux temp for 5 hr. The reaction mixt was worked up as above and the crride free base in Et20 was converted to the hydrochloride with ethanolic Recrystn from HC1 giving 3 4 . 3 , ~of crude salt, mp 125-129'. EtCOMe yielded 22.7 g (.io%) of white crystals of ,V-allylbenzylamine.HC1,13 mp 145-146".
which soon crystd giving 29 g of white solid, mp 70-90". Recrystn from i-PrOH-HZ0 gave 20.2 g of white solid, mp 86-98", A s o h of this base in 300 ml of EkO acidified with ethanolic HCI gave gummy hydrochloride. This was recrystd from 300 ml of i-PrOfi, yielding 10.3 g of white crystals, mp 199.5-201.5'. a-(2-(Benzylideneamino)-1-methylethyl]benzhydrol (41 ).-A s o h of 24.1 g (0.1 mole) of 1 and 13.2 g (0.12 mole) of PhCIIO in 100 ml of PhH was refluxed with a Dean-Stark trap for 45 min by which time the theoretical amt of HzO had sepd. The soln was evapd to dryness in vacuo giving a cryst residue which was recrystd from 250 ml of i-PrOH yielding 29.4 g of white needles, mp 132-136". l,l-Diphenyl-Z-methyI-3-(N-benzylamino)propanoI (42).-To a suspension of 33 g (0.1 mole) of Schiff's base 41 in 250 ml of MeOH, 7.6 g (0.2 mole) of N a B K was added portionwise with stirring under reflux. The mixt was heated for 1.5 hr more and the hleOH was evapd. The solid residue was mixed with 1120 and Et20 slid acidified with HC1. A n oily hydrochloride Femained insol in both layers. The oil and the aq layer were sepd from the E t 2 0s o h and the Et.20was repeatedly extd with dil IIC1. The combined aq s o h and oil were basified with NaOH giving 31.7 g of white solid, mp 104.5-106.5'. This was recrystd from 17.5 ml of i-PrOH yielding 30.0 g of white crystals, mp 106-108". 1,l-Dipheny I-2-methyl-3- (3,4,5-trimethoxybenzylamino)propanol (43).-A soln of 12.05 g (0.05 mole) of 1 and 9.81 g (0.05 mole) of 3,4,5-trimethoxyberisaldehydein 100 ml of PhH was refluxed with a Dean-Stark trap iiritil t,he t,heor amt of 1120was collected (about 0.5 hr). The PhH solrr was evapd giving the benzylidene compolirid as a yellow gum. This was dissolved in 150 ml of abs EtOH and hydrogenated with 0.1 g of Pt02 and 2 g of lOycPd/C a t 3 3 kg/cm2 and room temp. After 22 hr, the theor amt of HP had been absorbed, the s o h was warmed to dissolve a little solid and was filtd. The filtrate was concd to 130 ml, giving 1.5.9 g of white solid, mp 119-122'. This was recrystd from 100 ml of EtOH, yielding 14.9 g of white crystals, mp 120-
iC'-(3,3-Diphenyl-3-hydroxy-2-methylpropyl)butyramide(29). -To 24.1 g (0.1 mole) of 1 and 9 ml (0.108 mole) of Et3N in 1 I. of abs Et20was added dropwise 17 ml (17 g, 0.108 mole) of
N - (3,9-Diphenyl-2-methyl-3-hydroxypropyl)-a,~-dimeth~l-~alhnide (51).-A s o h of 12.06 g (0.05 mole) of 1 and 5.0 g (0.05 mole) of pivalolact.onel4 iri 100 ml of hIeOI1 was allowed to stand a t room temp for 3 days and then evapd in vacuo. The residue was boiled with 110 ml of i-PrOH and the product, was recrystd from 75 ml of D l l F giving 7.0 g of white solid, mp 233.5-235.5". N - (3-Hydroxy-2-methyI-3,3-diphenylpropyl )-p-toluenesulfonamide (54).-A soln of 24.1 g (0.1 mole) of 1 in 1 1 . of Et& was added t o a mixt of 21 g (0.11 mole) of TsCl in 100 ml of E t 2 0 and 4.4 g (0.11 mole) of NaOH in 50 ml of 1-120. The mixt was stirred under reflux for 3 hr, cooled, and washed (dil IlCl and dil NaOH). Evapn of the E t 2 0 gave nearly white solid which was recrystd from RIeOtI, t.hen from EtOAc, and finally from PhH, yielding 16 g gf white solid, mp 140-141". Even though this is a monosribstituted sulfonamide, it is nearly insol i n dil NaOld. N - Allyl-N- (3,3-diphenyl-2-methyl-3-hydroxypropyl )benzenesulfonamide (55).-To a s o h of 24.1 g (0.1 mole) of 1 in 500 ml of dioxane was slowly added with stirring ?5.3 g (0.2 mole) of PhS02Cl driring 30 min. 1)uriiig this addn 131 ml (0.25 mole) of .iOyoNaOH, dild with 200 ml of 1120, was added i n 4 portions. After stirring for an addl 30 min, 30 g (0.25 mole) of allyl bromide was added. The s o h was refluxed for 2 hr more and concd to a small vol in vacuo, giving 48.5 g of crude product, mp 110-1 18". This was dissolved in EttO, washed (dil NaOH, H20, satd NaCI), dried (Na2S04),and evapd. The residue was crystd from 200 ml of i-PrOH yielding 31.6 g of white crystals, mp 122-124". Fluorene-Ag,y-propyla~ine.HBr(58).-Crude B-(g-hydroxyfliioren-9-y1)propioriitrilewas prepared by the method of Campbell and Fairfull.16 I t failed to crystallize but was reduced with LA11 as described for 1. Attempts to isolate the expected 3-(9hydroxy-9-y1fluoren)propylamine either as the free base of hydrochloride failed but conversion of the crude free base to the hydrobromide gave a small yield of the dehydrated product. This was recrystd from EtOH and twice from H20, yielding 3.3% overall of light brown crystals, mp 252-25*5" dec. 5-(2-Amino-l-methylethyl)-2H-dibenzo[a,d] cyclohepten-5ol.HCI (60) WBS prepd by the method iised for 1 tiring 0.4 mole of I,iNEt216 in place of NaNIf?, 70 g (0.34 mole) of .iH-dibenso[a,d]cyclohepten-.iorie i n place of Ph?CO, arid 22 ml (0.4 mole) of EtCN i n 500 ml of E t 2 0 . The crude nitrile was redriced with
PrCOCI. After stirring under reflux for 2 hr, the reaction mixt was poured into ice water and acidified with HCl. The Et20 layer was sepd, washed (dil NaOH, H?O), and dried (K2CO3). The Et20 soln was concd and on standing crystd, giving 1X.X g of white solid, mp 107-109'. 1,l-Diphenyl-2-methyl-3- (1-cyclopropylethylamino)propanol (Racemate A ) (35).-A mixt of 12.1 g (0.0394 mole) of 34 and 1.9 g (0.05 mole) of NaBI14 in 125 ml of ;\le011 was allowed to stand for 2.5 hr and then heated iirider reftrrx for 2 hr. Rlost of the MeOII was evapd in vacuo. The residue was dissolved in cold dil HCI and washed well (EtZO). The aq soln was basified with NaOH and the resulting oil was extd with EtZO. The exts were washed (HnO, satd NaCI) and dried (Na2S04). After filtn and removal of the EtCO, the free base was crystd from 30 ml of pentane, yielding 3.7 g of cryst base, mp 92.5-96.5'. Recrystn from pentane raised the mp t o 99-101'. I r and nmr indicate this is essentially one isomer (racemate A). 1,l-Diphenyl-2-methyl-3- (1-cyclopropylethylamino)propanol (Racemate B ) (37).-The filtrate from base 35 was coricd to a very small vol, giving cryst of a second racemate which was recryst.d from 50% i-PrOH, mp 6X-71". I r and iimr spectra are very similar t o brit not identical with those of racemate A, indicating this is essentially the other racemate. 1,l-Diphenyl-Z-methyl-3- (cyclobutylamino)propanol HCI (38).-A sohi of 24.1 g (0.1 mole) of 1 and 14.0 g (0.2 mole) of cyclobutanone in 15 ml of PhlI was refluxed with a Dean-Stark trap for 20 min. The s o h was evapd in vacuo giving crude a[2-(cyclobritylider1eamino)-l-methylethyl]beii~hydrol as a waxy solid. This was dissolved in 250 ml of hIeOI3 and 7.6 g (0.2 mole) of NaBH, was slowly added portionwise. After refluxing for 3 hr, most of solvent was evapd in vacuo, and the residue was shaken with Et20 and cold dil HCI. An oily hydrochloride remained insol in both layers. The aq layer and oil were sepd, washed (Et&), and basified with NaOH. The free base sepd as an oil
.
(11) R . E. Lutz, P . S. Bailey, R. J. Rowlett. J. W. Wilson, R. K. Allison, M . T. Clark, N . H. Leake, R. H . Jordan, R. J. Keller, and K . C . Nicodemus, J. O w . Chem., 12, 760 (1947). (12) A. Sh. Sharifkanov and P. S. Ibranov. K h i m . Khim. Tekhnol.. Alma-
A f n , 1, 6 (1963); Chem. Abnfr., 61, 13274/ (1964). (13) S. L. Shapiro, V. A . Parrino, a n d L. Freedman, J . Amer. Chem. Soc.. 81, 3728 (1959).
123'.
(14) T h a n k s to E a s t m a n Chemical Products Co. for a sample. (15) N. Campbell and A. E. S. Fairfull, J. Chem. Soc., 1239 (1949). (16) Prepared i n situ by mixing equamolar a m t s of n u Li and EtCNIi.
1106 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
16.8 g (0.46 mole) of LAH, and treatment of the EtzO soln of the crude free base with 5% aq HC1 gave cryst hydrochloride insol in both layers. It was collected, dried, and recrystd first from a mixt of 2-PrOH and EtOH and then from EtOH yielding 18.5 g of white crystals, mp 280-281'. Free Base 59.-A sample of the hydrochloride was converted to the free base with NaOH and recrystd from methylcyclohexaue giving white crystals, mp 178.5-179.3'. 9-(2-Amino-l-methylethyl)-lO,lO-dimethyl-9-ant~o~maleate (61) was prepd from 22 g (0.1 mole) of 10,10-dimethyl-9-anthrone and 6.6 g (0.123 mole) of E t C N by the method used for 1 using
KEASLING AND MOFFETT 0.12 mole and L i N E t P in place of the NaNHZ. The crude free base was isolated as an oil, dissolved in EtzO, and acidified with a slight excess of ethanolic maleic acid. The resulting maleate salt was recrystd from 100 ml of i-PrOH, yielding 18.8 g of light tan crystals, mp 154-15.5' dec.
Acknowledgments.-The authors wish to thank our Physical and Analytical Chemistry Unit for analytical and spectral data, Mr. R. F. Tripp for technical assistance, and Dr. R. V. Heineelman for guidance.
Central Nervous System Agents. 3.' Structure-Activity Relationship of a Series of Diphenylaminopropanols HUGHH. ICEASLING AND ROBERT BRUCEMOFFETT* Research Laboratories, T h e Upjohn Company, Kalamazoo, Michigan 49001 Received March 12, 1971 A series of diphenylaminopropanols was evaluated for acute toxicity, anticonvulsant, anorexigenic, and anticholinergic activity as well as effect on simple reflexes. Therapeutic ratio was maximized in 1,l-diphenyl-2methyl-3-aminopropanol , HC1 (11-2). Anticholinergic activity was minimized by the presence of a 2-Me group. In general, tertiary amines were less active as anticonvulsants and on simple reflexes, than primary or secondary amines. Also increasing the size of the substituents on the amine decreased activity. Substitution on the Ph rings decreased activity except for the m-F derivative which was more active than 11-2 but also more toxic. The optical isomers of 11-2 were resolved and the 1 isomer (11-6) was no more toxic but markedly superior in activity.
The synthesis of a series of diphenyl aminopropanols which we have studied is reported in the two preceding communications.' Our interest in the compounds was due to their unique dose-related spectrum of pharmacologic activity. Administration of one of the more potrnt analogs to a variety of species produces apparent stimulation at low doses. At slightly higher doses the cffcct is one of mixed stimulation and depression with markcd motor incoordination. I n this dose range some of thr compounds appeared to be potent anticonvulsants. Still higher doses produce convulsions in rats and mice and an apparent paralysis with ocassional clonic twitching in cats and dogs. Because of this spectrum of effects, structure-activity studies had to include a broad spectrum of tests. For this reason, testing inrluded effects of the compounds on anticonvulsant and anorexigenic end points as well as effects on several simple rc4exes. Anticholinergic testing was also included since many diphenyl aminopropanols are knoivn cholinergic
(1) .\rticles 1 and 2 : R. B. RIoffett. R. E. Struhe, and L. L. Skaletaky, J . .Wed. C h e m . , 14, 1088 (1971); and R. B. Rloffett and T. L. Pickering, zbid.. 14, 1100 (1971). T h e numbering of compounds in this article refers t o t h a t used in t h e preceding articles. I refers t o Tahle I in article I. I1 refers t o Table I in article 11. Compounds designated I11 have been previously reported (see ref 2 and footnotes in tables).
blocking agents.2 Although it is not known which, if any, of the CNS effects are mediated by a cholinergic mechanism, it was hoped useful compounds could be found by maximizing the CNS effects while minimizing the peripheral effects. Methods.--i\lale albino mice of the Carworth Farms strain (18-22 g) and adult mongrel dogs were used in all studies. For studies in mice, compounds were suspended or dissolved in 0.25% aq methylcellulose and administered ip. At least 3 dose levels spaced at a 0.3 log interval were used for each end point. The effective dose (ED50)was calcd by the Spearman and Karber meth~d.~ Procedures for measuring acute toxicity (LDbo), antagonism of nicotine seizure (1\T5~), and antagonism of isolation-induced stress (FRIjo)have been described.* The same source also describes methods for evaluation of compounds on simple behavioral reflexes-traction (2) (a) J. J. Denton, H. P. Schedl, W.B. Neir, and V. A. Lawson, J . Amer. C h e m . Soc., 71, 2054 (1949); (b) R . W. Cunningham, B. K. Hained, M . C. Clark, R . R. Cosgrove, S . S. Daugherty, C . H. Hine, R . E. Vessey. and S . N. T d a , J . Pharmacal. E x p . Ther., 96, 151 (1949); (0) D. W. Adamson. J . C h e m . Soc., S u p p l . , 6 , 1 4 1 (1949). (3) D . J. Finney, "Statistical Methods in Biological Assay," Hafner Publishing Co.. New P o r k , N. Y . , 1952. (4) G. A. Youngdale, D. G. Anger, iV. C. Anthony, J. P. DaVanro, 11. E. Greig, R . V. Heinzelman, H. H. Keasling, and J. Szmuszkovice, J . M e d . C h e m . , 7, 415 (1964).
