NEW COMPOUNDS
January lBGS
195 T.4.BLE 1
Experimental Sections Transformation of 2~-Methyl-lS-nortestosteroneby A . tamarii. -To each of 14 erlenmeyer flasks, each of which contained 100 nil of a 3% Difco malt extract solution and a 48-hr growth of .l. tamarii, was added 75.0 mg of 2~-niethyl-19-norteatosteroneg i i i 0.4 ml of DL2F. After an additional 72 hr of incubat'ioii o n a rotary shaker a t 28", each reaction mixture was extracted with CH2C12. The organic layers were combined, dried (XgSO,), aiid evaporat,ed t,o a dry residue (1034 mg). A portion of the latter (1005 mg) was chromatographed on a 90-g column of silica gel H with EtOAc as the eluent. Tlc of the eluent fractions indicated that, three major fractions were obt,ained. Fraction 1 (150 mg) was starting material, 2a-met,hyl-19-nortestosterone. Fraction 2, after recrystallization from lle2CO-hexane, produced 675 mg (68y0 yield) of 2a-methyl-19-nort~estololactone: mp 191-192.5'; vZ89: 1725, 1670, and 1620 cm-1; nmr ( c n c l , ) , 6 1.10 (3 H), 1.38 ( 3 H), and 5.83 (1 11); [ a I z 5+13" ~ in cI3C1,. .-Inal. Calcd for C I O I T ~ ~ C, O ~73.46; : H, 8.67. Found: C, 75.45; 11, S.64. Fraction 3 (180 ing) coiisisted of mixttires of the above steroids aiid trace amounts of other compounds which are probably additional oxidative metabolites of 2a-methyl-l9-riortestosterone, contaminated with CH~Clz-xolublecellular material. Acknowledgment.-This work was supported in part by a University of Tennessee Instit~utionalAmerican Cancer Society grant. (8) All melting points were determined b y a Kofler apparatus and are rorrected. (9) Generously supplied b y Dr. Paul \V. O'Connell. T h e Upjohn Co., Iialamazoo. hlich.
Application of 1,3-Di(4-piperidyl)propane in the RZannich Reaction. Synthesis of @-AminoKetones It IJENDRA S. VARMAASD W.LEWISNOBLES Department of Pharmaceutzcal Chemistry, Cniaersit y of Mississippi, University, Mississippi
38677
Received J u l y 20, 1967 p-Aiiiirio ketoiies (llariiiich bases) have been reported to possess antispasmodic,' analgetic,2 local anestheticJ3-6 aiid antibacteria17-'0 activity. In a recent communicationll from this: laboratory we described the synthesis of a series of 8-amino ketones derived from l-(N-p-hydroxyethyl-4-piperidyl)-3-(4piperidy1)propane. Several of these compounds have exhibited antibacterial and antiviral activity. l 2 Ready availability of 1,3-di(4-piperidyl)propane (4-DI-PIP) prompted 11s to prepare @-amino ketones of this novel secondary amine for biological screening. Screening Results.-The compounds of Table I were screened in vitvo against four organisms : Pseudomonas aeruginosa, Staphylococcus a u ~ e u s ,Mycobacterium smegmatis, and Klebsiella pneumoniae. Filter paper disks (6.35" diameter) saturated with the solution (20 mg/ml) of the test compound were placed on the agar. After 72 hr of incubation the zones of inhibition around the disks were measured. The results are reported in Table 11. (1) J. J. Denton, R. J. Turner, \V. 13. Neier, V. .I. L a w o n , and 11. P. Scliedl. J . Am. Chem. SOC.,71, 2048 (1949). (2) U. S. Patent 3,030,372 (April 1 7 , 1862); Ckem. Abatr., 69, 2780 (1963). (3) C. Mannicli and D. Lammering, B e r . , 66, 3810 (1922). (4) F. F. Blicke and E. S. Blake, J . Am. Chem. SOC.,63, 236 (1930). (5) W.Wilson and 2. Y . B y i , J . Chem. SOC., 1321 (1952). (6) T. Teshigahara, N i p p o n Yakurigaku Zasshi, 68, 67 (1962); Chem. Abstr., 69, 3239 (1963). (7) H. J. Florestano a n d 11. E. Bahler, J. Am. Pharm. Assoc.. 46, 320 (1966). (8) W.L. Nobles and B. B. Thompson. J . Pharm. Sei., 68, 1554 (1964). (9) W.L. Nobles and C. D. Blanton, ibid., 51, 878 (1962). (10) J. Sam and A. C. Thompson, ibid., 63, 535 (1964). (11) R. Y. Varrna a n d \V. L. Xohles, ibid., 66, 456 (1967). (12) 11. 6 . Varma and 5V. L. Nobles, unpublished w0r.k
No. 1 2 3 4 5 6 7 8 9 10 11
R 2-Thenyl 4-Ethoxyphenyl 4-Hydroxyphenyl I-Nitrophenyl 4-Chloroplieny l 4-Hromoplienyl 4-l'luorophenyl 4-11ethylplienyl 3-Nitrophenyl 2-H ydroxyplienyl Phenyl
Xlp, OC" Tield, 212-215 55 184-185 44 245 43 200-20:3 35 209-2 12 81 212-215 69 190-194 42 195-197 65 180-183 49 21 1-212 28 210-212 48
-411 compounds melt with decomposition. Yields are of the product obtained after t'he first crystallization. Prepared by method C. d Prepared by method A. e Prepared by method B. Recrystallized from EtOH; the other compounds were recrystallized from Et0H-lIe2CO-H2O. g All compoiuids were aiialyzed for C, I T , N. Iiifrared abuorptioii baiids for XII+ aiid C=Owereasexpected.
T.WLEI1 I n Vitro ANTIBACTEILIAL ACTIVITY c -
S . aweus KO.
1 2
K257
++
O F P - h f r ~ oKETOKES 1licrol)iaI spectrum" K. pneumonzae M. P . aerwinosa A T C C 8052 smegmatis
+ +
-
-
+ +
4 5 6 7 8 9 10 11
A iiegative sign indicates no observable activity. Experimental Section'3 1,3-Di( 4-piperidy1)propane Dihydrochloride.-4-DI-PIP (42 g) was suspended in 100 ml of EtOH. Concentrated HC1 (40 ml) was added dropwise with cooling and stirring. After the additions were completed, hfe2C0 (200 ml) was introduced into the reaction vessel. The reaction mixture on refrigeration overnight furni3hed the desired salt in nearly quantitative yield. The salt was recrystallized (EtOH-lIeLCO); mp 262-264" dec. -1nal. (CldH&12N2) C, HI N. 8-Amino Ketone Dihydrochlorides. Method A.-A mixture of 0.04 mole of the appropriate ketone, 0.02 mole of 4-DI-PIP dihydrochloride, 1.8 g of paraformaldehyde, and 50 ml of EtOH containing 2 drops of concentrated HCl wa5 refluxed for 5 hr. The warm solution was poured into hIe2C0 (100 ml). Overnight refrigeration of the contents yielded the desired product. Method B.-Concentrated H C l ( 4 ml) was added dropwise to a cooled suspension of 4-DI-PIP (4.2 g, 0.02 mole) in 10 ml of EtOH with shaking. Aqueous formaldehyde (377, 6 ml) was then introduced into the reaction vessel followed by the appropriate ketone (0.04 mole). The resulting reaction mixture was heated at 90-100" for 6 hr. During this time the entire mixture went into the solution. In a few cases an amorphous solid product separated a t the end of this period. The contents were then diluted with Me2C0 (100 ml) and refrigerated overnight or until a solid product separated. Method C was similar to that of R except that parafornialdehyde was used in place of formalin. Acknowledgments.-Thii iiivestigation wab supported in part by Grant 04701 from the National Institute of Health, U. 8. Public Health Service, Rethesda, &Id. The authors gratefully acknowledge the facilities and assistance provided by Dr. Lyman Magee and RIr. William Bing during antibacterial screening. ( 13) All melting points were taken on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Microanalyses were performed b y Galbraith Laboratories, Inc., Knox\,ille, Tenn. Infrared spectra were recorded in Nul01 mull on a Perkin-Elmer Model 137 Infracord spectrophotometer and were a s expected. IVhere analyses are indicated only by symbols of the elements analytical results obtained for these elements \\ere within rt0.4V0 of t h e theoretics1 valuea.
