Acknowledgments.-The :tuthors are indebted to the following perwnk for their cwitributioiis to thi. work :
iiitcri)ret:tti o i i - , ~ i n d1)r. Iiiice an intermediate carbonium ion and primary chloride 6c separated by column chromarenter would be generated at either of these positions. tography. The crude mixed product of tosylation ivas cyclized as in the six-membered series nith potassium t-butoxide in refluxing f-butyl alcohol to give :3’,4’-dihydro-3-methoxyestra-l.3,9( lO)-trien- 17,2’12‘H)-oxete (la). When subjected to the modified Birch rcduction 11-ith Li-SHJ, la u-as coiiverted to the 1,4dihydro enol ether 2. However, all attempts at acid hydrolysis of 2 to obtain the 3-l;eto-A4 or 3-ltet0-A~‘~~’ derivative with retention of the strained four-membered spiro ring a t C-17 failed. Work-up of an HC1-aqueous methanol hydrolysis of 2 yielded a rearrangement produc t assigned as 17a- (2-h ydroxyet h yl)- 1ip-met h ylgo na4,13-dien-3-one (loa) o n the basis of infrared arid nmr spectra. 20 It appeared of interest to prepare additional steroid structures having the A13- 17a-hydroxyalIiyl-l7@-methyl moiety and, since in the presence of acid. lip-hydroxy17a-alkyl steroids are linotvn t o dehydrate n ith migration of the 13-methyl the aromatic ;2-ring diol
ACHJ
Zla, R = H b, R = CH
10a,n=l; R=II b , n = 2 , R=H c n-2; R = C H :
9 a , ny=1 b,n=2
CH ,O
fl 13a, n = l b,n=2
H
O
W
14
22
In addition, both 18 mid 1 3 la?l;ed hydroxyl absorption in the infrared. The iiixr spectrum for t h e fivemembered cyclic ether 13a had :I multiplet centered zt 223 cps (partially obsriircd hy t h e methoxyl peak)’ for the protons next to the ether oxygen and the C-17 methyl protons peak at C,S (ys. The six-membered ryclic ether 18 had a less symmetricnl multiplet centered at 217 caps and the C-17 methyl ped; was nt 3s cps. E r i d e r m for the nsigrirrierit of 18 :is a sismembered ring ether cmie from the fact that n-hen it \vas oxidized with c.hrcimium trioxide-aretic :wid tlie crude product had a n infrared :Lbsorptic:n baiid at 5.77 p , characteristic of n &l:wtoix. Li-SH, reduction of 18 produced the enol ether 19 which wheii iiydrolyzcd with 9OYc acetic acid gave the 3-lieto-.15t10’ derivative 20 and when hydrolyzed and then is;omerized with dilute HC1 in methanol gave l~.li?-el,oxy-lic-ethyl17@-methyl-13~-goii-~-en-3-one (21a). Similarly, LiS H , reduction of 13a pave the enol ether 14. hydrolyzed t o 15, and 1~ydrolyzt.d:uid ihomerized t o 13,172-epoxy-17a-ethyl-1i~-~iiet 113.1 - 1 3 u - p o r i -1-en -;-Ione (lea).
Surprisingly, TI hen 8, liaving thc ctliy! ;L(,(>t:it(’side chain at C-17, n-as suhjccted to rencatioii wit11 HC1 in refluxing ethanol, 110 clehydrntioii iii~-olvi ng thc 17P-hydroxyl group occurred. The start ing mat crinl TWS totally recovered. I o explnnutiou for this 15 16a.n=l: R-H anomaly is immediately ai-parcnt init SI apratli , b, n = 1: I? CH, ‘7. p, -~ - cy . .., et al.,!j reported difficulty in dehydrating the an:ilogous ethyl %-(3,~-acet(~xy-1‘7p-h~droxyalldrc1.;t-.i-eri-17a-y1)6a was subjected t o reaction with HCl in refluxing acetate. T o disprove the hypothesis that successful ethanol. From this reaction, in addition t o the exdehydratiori-rearrangement using the roridit ic )lis repected 17a-(2-hydroxyethyl)-3-methoxy-l7@-methyl- ported herein required the presenre of t h e terniiiial gona-1,3,5(lo), 1Btetraene (9a), column chromatoghydroxyl group on the alkyl side chaiir a t C - l i , l i u raphy yielded two other products n hich have been ( i )The position i a clearly e\-ident in tlie deri\-atiri. 16a ~ \ l : i c . I i does not assigned as 14,17-epoxy- 17wet h yl-3-met hox y- 1ip-met h=
=
(6) V. Tortorella, G . Lucente, a n d .\. Romeo. A n n . Chim. (Rome), 60, 1198 (1960).
h a r e a metlioxJ-l w o n r J . (8)D. Alagratli, D. S. liorvih, 2393 (1950).
Y. P e t r o n . and K. 1ioyt.r. J . L‘irern.
Sue,
AXTIESTROGEN CYCLICSTEROIDAL ETHERS
July 1967
549
144-149'; nmr, 50 (18-CH3), 61 (19-C&), ca. 220 (multiplet, 23-CH2 and 3aH), 320 (6-H) cps. Anal. Calcd for C?3H&: C, 80.16: H, 10.53. Found: C, 80.01; H, 10.40. 3',4 ',5',6'-Tetrahydrospiro[androst-4-ene-17,2'( B'H)-pyran] %one (3c).-A reaction mixture of 350 mg of 5, 350 mg of aluminum isopropoxide, 3 ml of cyclohexanone, and 20 ml of toluene was stirred at reflux under N2 for 30 min. The solution was cooled, 1.3 ml of saturated aqueous Rochelle salt solution was added, and then it was steam dist.illed for 30 min. The granular precipitat,e which formed on cooling was collect,ed, washed with 3',4',5',6'-Tetrahydrospiro[3-methoxyestra-l,3,5( 10)-trieneH20, dried, aiid recryst,allized from et,hyl acetat,e to yield 200 17,2'(2'H)-pyran] (lb).-A solution of 3.0 g of 6e and 3.0 g of mg of 3c: mp 170" (aft,er prior sublimation); 3':!A: 5.98, 6.19 j ~ ; p-tolueriesulfoiiyl chloride in 30 ml of pyridine was held a t room , , ,A 241 mk (E 14,450). temperature for 90 hr and then transferred into 150 ml of ice Anal. Calcd for CzaHa402: C, 80.65; H, 10.01. Found: C, water. The precipitated gum was extracted with ethyl acetate 80.98: H, 10.03. and the solution was washed twice with water and twice with Ethyl 2-[17p-Hydroxy-3-methoxyestra-1,3,5( lO)-trien-17a-y1] dilute acetic acid. After it was dried (Sa,SO,), the solution was acetate (8).-A reaction mixture of 10 g of estrone 3-methyl evaporated to 1 . j g of oily residue. This residue, together with ether, 22 g of ethyl bronioacetate, 14 g of 20-mesh zinc (pretreated 1.5 g of potassium t-butoxide, was dissolved in i 5 ml of t-butyl successively with dilute HCI, H!O, methanol, dry ethyl ether, and alcohol niid the sulutioii was refluxed for 2 hr. After standing dry benzene), and 100 ml of dry benzene was stirred and heated 4 days at room temperatiire it was diluted wit,h 100 ml of ethyl to refliix whereiipon an exothermic react,ion begaii and coiit,inued ether aiid ext,racted with four 25-ml portions of water. The iinder cont8rolfor 15 mill withoiit external heat.. Heat, was then c ~ ~ m b i n eaqiieoiis d washings were extract.ed wit,h 50 ml of ether applied to mailitmainreflux for 2 hr aft.er which t,he reaction mixaiid the et,her ext,ract was washed twice wit.h wat,er. The nonture was decanted from t.he \inreact,ed zinc and into 500 ml of cold nqiiroiis solutioiii were then combined and dried (Na2S04). 2% HCI. The henzene layer war separated arid combined with 1:vaporation ~f solvents afforded an oily residue which crystalan ether extract of t.he aqiieolis layer. The combined ether and lized overnight, and Fa-: recryst,allized from ethyl acetate to benzene solutions were washed with water, dried (Sa2S04),aiid yield 700 mg of lh: m p 108-110": 6.21, 6.33, 6.62, 9.26, evaporated. The oily residue was dissolved in 80 ml of ethanol, 0.62 p ; ,,:A, 278 mp i c 2110): nmr, 52 (18-CH3), ea. 225 (mul8 g of trimethylaminoacet,ohydrazide chloride (Girard's reagent) t,iplet,23-CHs), 227 (OCFT,) cps. and 8.0 ml of acet,ic acid were added, and the solution was reI n d . Calcd for C~:IH&: C, 81.13; H, 9.47. Found: fluxed for 30 min and then t,ransferred into a solut'ion of 12 g c, 81.31: 13. 9.54. of NaHC03 in 400 ml of HzO. After 18 hr at, 5' t,he precipitat,e 3',4',5',6'-Tetrahydrospiro[estr-4-ene-l7,2'(2'H)-pyran]&one was collected, washed wit8hH,O, dried, and recrystallized from (3b).--Lithium wire (1.2 g ) was added over a 10-min methanol to yield 5.i5 g of 8: mp 102-104'; 3':;A: 2.88, 5.83 p. period to a stirred solution of 1.75 g of lb i n 60 ml of T H F , Anal. Calcd for c23H3?04: C, 74.16; H, 8.66. Found: 60 ml of t-hutyl alcohol, aiid 120 ml of liquid "3. After 2.5 hr C, 73.83; H , 8.35, the reaction mixture had decolorized and 5 ml of methanol was 17p-Hydroxy-l7a-(2-hydroxyethyl)-3-methoxyestra-1,3,5(10)added. Ammonia was allowed to evaporate for 2 hr and 100 ml triene (6a).-A suspension of 2.5 g LiAlH, in 100 ml of anhydrous of HIO was added. Sonaqueous solvents were removed by ethyl ether was stirred and refluxed for 30 min. A solution of vacuum diatillatiori and the residual aqueous suspension was 5.0 g of 8 in 110 ml of anhydrous ethyl ether wa,s added over filtered. The solid prnduct was washed with H 2 0 and dried to 10 min and then refluxing and stirring a e r e resumed for 3 hr. yield 1.7 g of r u d e 1,4-dihydro product, 1.0 g of which was After 10 nil of et,hyl ether satiirated with HzOwas added dropwise, .dirred in 10 ml of methanol with 0.5 ml of H 2 0 and 0.6 ml of 3 nil of H2O was added caiitioiisly and the slurry was filtered. concentrat,ed HC1. Stirring was continued for 1 hr a'id t,he reConceiit,ratioii of t,he filt,rat,eprovided 280 mg of 6a, mp 158-160". siiltipig holiitioii nay transferred irit,o 100 ml of H?O. The The insoliibles were stirred for 3 hr with 200 ml of HfO, 2.5 ml aqiieoiis hiispeii;.ion was extracted wit,h et.hyl acetate and the ethyl acetate layer waa washed with H 2 0 and dried (Sa2S04). of concentrated HC1, and 100 ml of CHC13. The CHCL layer was separated, washed wit,h HzO, dried, and evaporated t,o Evaporat,ivii of solvent aff'orded a n oil which crystallized slowlv. yield 3.9 g of 6a,mp 162-163'. tallizat,ioii from et,hyl acetate-hexane provided 230 mg of 17D-Hydroxy-l7a-(2-chloroethyl)-3-methoxyestra-l,3,5( 10) 3b: mp 126-130'; A",tl,"" 5.99, 6.16 p :, , ,A 240 mp ( e 15,550). triene (6c) and 17~-Hydroxy-l7a-(2-p-toluenesulfonyloxyethyl)Anal. Calcd for C22H&: C, 80.44: H, 9.83. Found: C, 3-methoxyestra-l,3,5(1O)-triene(6b).-A solution of 800 mg of 80.24: H, 9 , i i . 6a,800 mg of p-toluenesulfonyl chloride, and 8 ml of pyridine was 17a-(4-Hydroxybutyl)-5-androstene-3p,17p-dioI(7b).-To a held a t room temperature for 18 hr and then transferred into stirred suspeiisioii of 3.3 g of LiAlH, in 150 ml of T H F was added 100 ml of ice water. The precipit,at,e was collected, washed with over a 10-mill period a solution of 9.8 g of 4-(3p,lip-dihydroxyH,O, dried, and chromatographed. The first peak fract'ion 5-androsten-17a-y1)butanoic acid lactone4 in 250 ml of T H F . eluted with 2yc ethyl acetate-benzene was recryst,allized from Reflux with stirring LTas maintained for 2 hr and then a solution benzene t'o yield 100 ma of 612,mp 168-170", A": 2.80 U. of 2 ml of HzO in 28 ml of T H F was added dropwise, followed by Anal. Calcd for CiIH2sC10?! C, i2.40; H, 8.38. Found: 15 ml of H,O dropwise. The reaction mixture was filtered and C, 72.17; H. 8.27. the filtrate was evaporated to a residual volume of 250 ml and A4secondary peak from elrit,ion wit,h 2% ethyl acetate-benzene cooled to j0 producing 3.4 g of 7b. Further evaporation of was recrystallized from et,hyl acet.at,e to yield 50 mg of 6b, mp solvent yielded 1.9 g of a second crop. Recrystallization from a 147-148'. d n a l . Calcd for CpaH,,068: C, 69.39; H, 7.49. large voliime of ethyl acetaw provided an analytical sample: mp Fourid: C, 69.54; H, '7.58. "4-227": :3.02, 5.$)*p , 3',4'-Dihydro-3-methoxyestra-l,3,5(10)-trien-17,2'(2'H)-oxete .-lna(. Calcd for C T ~ H B B O C,~ i6.19; : H, 10.57. Fonnd: C, -(la).-To a solution of 7.5 g of the crude reaction product, r 0 . 0 2 ; €I, l l ) , 2 i , from the treatment of 6a with p-toluenesulfonyl chloride (see 3',4',j',6'-Tetrahydrospiro[androst-5-ene-l7,2'(2'H)-pyran] 6 b and 6c) in 350 ml of t-butyl alcohol was added 7.5 g of po3/3-01(5).-A solution of 3.4 g of 7 b and 3.4 g of p-toluenesultassium t-butoxide. After 3.5 hr of stirring a t reflux the cooled fonyl chloride in 60 ml of pyridine was held a t room temperature reaction mixtiire was diluted wit,h 500 ml of ethyl ether. The for 18 hr and then transferred into 500 ml of ice water. The upper layer was separated and washed with four 250-ml port,ions solid precipitate was collected, washed with H 2 0 , dried, and, of water. The combined water washes were extracted with t,ogether with 3.0 g of potassiiim f-butoxide, dissolved in 115 ml of 200 ml of ethyl ether. The combined nonaqueous solvent layer l-biit,yl alcohol. The solution was reflrixed for 2 hr, cooled, was dried (NanHO,) and evaporated and t,he solid residue was diluted with 300 ml of ethyl ether, and washed in a separatory fiinnel with H20 five times and then finally with satiirated h-aC1. recrystallized from benzene-hexane t,o yield 3.55 g of la: mp 109-110'; nmr, 48 (18-CH3), 227 (OCH,), 265 (multiplet8, 21Aft>erit was dried (KaaSO,) the s7lvent. was evaporated to a 2.9-g CH?)CPS. residue which was sitbject,ed t ) chromatographic separat,ion. The fractions eluted with 10% ethyl acet.ate-benzene were comAnal. Calcd for C21H2~02: C, 80.73; H, 9.03. Found: bined and recrystallized from n-hexane to yield 510 mg of 5, mp C, 80.82; H , 8.96.
solution of 2.15 g of 4-[17p-hydroxy-3-methoxy-1,3,5( 10)-estratrien-1iaY-yl]butarioicacid lactone4 in 12 ml of dioxane was then added over a 10-min period. An additional 50 ml of anhydrous ethyl ether was added and then reflux with stirring was maintained for 4 hr. T h e cautious addition of 4 ml of water was followed by diliit,e HC1 unt,il an acid react,ion was achieved. The ,soliltion was decanted from t.he pasty residiie, washed twice with water, aiid dried (Sa2S04). Evaporation of solvent, left an oily residiie which crystallized when ethyl acetat,e was added. Recrystallization from ethyl acetate yielded 2.0 g of 6e, mp 127128", liqiiified at 88" and resolidified.
-
-
A:::
-
July 1967
551
7a-CHLORO-A-NOR STEROIDS
of saturated aqueous Rochelle salt solution was added, and the mixture was steam distilled t,o remove nonaqueous solvents. The solid precipitak was collect,ed, washed with water, dried, and recrystallized from ethyl acet,ate t,o yield 620 mg of 21b: mp 129-134'; 6.00,6.19 1.1. A n a l . Calcd for C21H300?: C, 80.21; H, 9.62. Found: C, 80.15: H, 9.48. Following tmheabove procedure identically, 1.0 g of 17 was oxidized and t,he crride react,ion product. was recrystallized from ethyl acet,ate t.o yield 480 mg of 16b: mp 144-150'; nmr, 68 (17-CHa), 7 2 (19-CH,), 225 (mnlt,iplet,, 21-CH2), 344 (4-H) cps. Anal. Calcd for CnlHaOOj: C, 80.21; H, 9.62. Found: C, 80.21; H, 9.37.
Anal. Calcd for C22H390?: C, 80.44; H , 9.83. Found: C, 80.69; H , 10.00. A solution of 800 mg of 11 in 8 ml of methanol with 0.6 ml of concent,rat,edHC1, and 0.6 ml of H 2 0 was held a t room temperature for 2 hr and then dilrited with 40 ml of H 2 0 . The precipit,ate was collected, washed with H20, dried, and recryst,allized from et.hyl acet,at,e to yield 10b (550 mg): mp 135-141'; 2.74, 6.00, 6.18 M ; A, 238.5 mp ( E 16,000). A n a l . Calcd for C21H300y: C, 80.21; H, 9.62. Found: C, 80.15: H, 9.59.
vents were removed by vacitum distillation and the precipitat,e was collected, washed wit,h HjO, dried, and recrystallized from et,hyl acet8at,econtaining 1 drop of pyridine to yield 1.3 g of 11 : nip 83-89' ; ?!A: 2.74, 5.88, 6.00 p.
Division of Biological Research for the biological data and Dr. Roy H. Bible, Jr., for interpretation of timr spectra.
Xz3 ;l
13,173-Epoxy-10,17fl-dimethyl-l7~-propyl-l3~-gon-4-en-3-one ( 16c) and 1 7 4 3-Hydroxypropyl)-lO,l7fl-dimethylgona-4,3-dien-
%one (10c).--A reaction mixture of 15 g of 17a-(3-hydroxy1 7 43-Hydroxypropyl)-3-methoxy-17fl-methylgona-l,3,5( lo),propy1)-4-androsten-lip-ol-3-one,360 ml of ethanol, and 15 ml 13-tetraene (9b) and 13,173-Epoxy-3-methoxy-17fl-methyl-17~-of concentrated HC1 was stirred aiid refluxed for 50 min during propyl-13~~gona-1,3,5( 10)-triene (13b).-A reaction mixture of which time solution became complete. \Tater (300 ml) was 25 g of 17~-(3-h~drox~propy1)-3-methoxy-1,3,5(10)-estratrien- added and the precipitat,e was extracted with beiizene and 17p-ol (6d)," 100 ml of et,hanol, and 25 ml of concentrated HCl chromatographed. The fraction eluted with 157,; ethyl acetate,tiired and refluxed for 45 min with solution being cumplete benzene was recr>-stallized from hexane to yield 2.35 g of 1 6 ~ . 10 miii. It, was cooled and st,irred, aiid 350 nil of cold H,O An analytical sample was ohtailled by a second recrystallizat,ion was added prodiiciiig an oil which congealed when cooled t,o 5'. from hexaiie: mp 100-105°; 5.9'1, 6.18 p ; nmr, 45 (17The oil was collect,ed, washed wit,h HZO, dried, and recryst>allized CH,), 72 i19-CHa), 222 (mriltiplet,, 22-CH?), 343 (4-H) cps. from et>hylacetate t,o give 8.0 g of 9b. A sample was recrystal=ln,al. Calcd for CyPH3.20P:C, 80.44; H, 9.83. Folnld: lized from acet,one for anal mp 85-90': 3'::A: 2.76 p ; nmr, C, 80.63; H, 9.89. 61 (li-CHa), 216 (triplet., 22-CH,), 226 (OCH,) cps. The oily peak fractions eluted with 4 0 5 et,hyl acetat.e-benzene =Inal. Calcd for Ca2H300y:C, 80.93; H, 9.26. Found: C, (8.44 g) Ivere critde 1Oc contaminated with a >mall amount. of t'he 80.74; H, 8.92. acetate ester of the C-22 hydroxyl group (from transest'erifica6ion The mot,her liqiiors from 9 b were chromat,ographed and t,he wit,h et.hyl acet,ate). A 2-g sample was dissolved in 20 ml of first fractioiis eluted wit,h lYc ethyl acetate-benzene were comwarm methanol, 5 ml of 2 7 , aqiteous KHCO, was added, and bined and recryst,allized twice from et,hyl acetate t,o yield 1.1 g after 5 hr at, room temperatiire 100 ml of HZ0 was added. The of 13b: mp93-95'; nmr, 44 (17-CH3), ca. 225 (mitltiplet, 22-CH?), separated oil was extracted with et8heraiid the et,her solution was 227 (OCH,) C ~ S . washed wit,h H10, dried (Xa,SO4), and evaporat,ed t.o yield 1.7 g Anal. Calcd for C Y ~ H ~ ~ O C,Y 80.93; : H, 9.26. Found: 2.73, 2.88, 5.98, 6.18 p ; Am,, 239 mp ( e 17,100); of 1Oc: C, 81.23; H , 9.22. nmr, 49 (17-CH3), 59 (lS-CHS), 216 (triplet 22-CHy), 345 (4-H) 1 7 4 3-Hydroxypropyl)-3-methoxy-l7p-methylgona-2,5( lo),13-triene (11) and 1 7 4 3)-Hydroxypropyl)-17fl-methylgona-4,- cps. Anal. Calcd for C2PHP2O2: C, 80.44; H, 9.83. Found: 13-dien-3-one (lob).-Lithium wire (1.6 g ) was added over a C, 80.33; H, 9.72. 10-min period to a stirred solution of 2.5 g of 9 b in 75 ml of T H F , 75 ml of t-butyl alcohol, and 150 ml of liquid "3. After 2.5 hr, 6 ml of methanol was added dropwise over 15 min with deAcknowledgment.-The author wishes t o thank colorizatioii of sol\it8ionaft,er 3 hr. NH, was allowed to evaporate for 2 hr and then 150 ml of HsO was added. Nonaqrieotts solDr. E. F. Sutting and N r . Roger Bergstrom of the
6-Chloro-6-dehydro-A-norSteroids w i t h Progestational Activity.
7a-Chloro-A-nor Steroids
PATRICK A. DIBSSI,SEYMOUR D. LEVIXE,IlXD
RAYMOND
11. PALAIERE
The Squibb Institute f o r X e d i c a l Research, S e w Brunswick, S e w Jersey
Received January 21, 1967 The synthesis of several 6-chloro-6-dehydro-8-nor steroids is described. Two of these compounds, 6-chloro6-dehydro-17a-acetoxy-A-norprogesterone(16)and 6-chloro-6-dehydro-l6a, lia-dimethylmethylenedioxS.-$-norprogesterone (14),are potent progestat~ioiislagents. These represent t>hefirst examples of A-nor steroids having this hormonal activity. Reaction of A3-2-keto-A-nor steroids with 2,3-dichloro-5,6-dicyanobenzoquinone and HCl results in the format,ion of 7a-chloro compounds as well as the 6-dehydro derivatives. The mechanism of this reaction is discussed.
Previously reported A-nor analogs of sterodial horrnones have shown litt'le or none of the biological properties of the parent hormones. Thus A-norprogesterone (1) l does not exhibit progestat,ional properties but is a potent antiandrogenic compound;2 A-nortestosterone (2)l is weakly a n d r ~ g e n i c ,and ~ A-
norhydrocortisone and A-norcortisone4 do not show the glucocorticoid or antiinflammatory properties of hydrocortisone or cortisone. The chemical modificat,ion of steroid structures designed t o enhance progestational activity has been the subject of much interest in recent years. I n certain
(1) F. L. IVeisenborn a n d H. E. Applegate, J . A m . Chem. Soc., 81, 1960 (1959). (2) L. .J. Lerner, A. Uianchi, a n d A. Borman, I'TOC. Soe. Erptl. Biol. .Wed.,
( 3 ) L. J. Lerrer, .\. 13ianctii, hl. Dzelzkalns, and A. Barman, I'roc. SOC. E r p t l . B i d . .lZud.. 115, 924 (1964). (1) R. Hirschmann, G . .I. I h i l e y , R . \\alker, a n d .J. 11.Cliernerda, J . A m . Chem. Sac., 81, 2822 (1959).
103, 172 (1960).
