STEROIDS.CCCX. HYPXOTIC AGEKTS
January 196s
benzamide (48) (14.0 g, 0.0475 mole) in redistilled POCl, (100 ml), arid the mixture was heated under reflux for 0.5 hr. The excess POCl, was removed under reduced pressure. il CHCl, solution of the residue was washed (aqueoiis K2C03, H20). The solution was dried (NanS04)arid the CHCL was removed. The residue was exharistively extracted with boiling Skellysolve B. The combined extracts were reduced in volume and cooled to yield 10.5 g (80.2(';,) of 65 as pale yellow needles, mp 129,3-132°. 5-(2-Anilinophenyl)tetrazoles.-All of the tetrazoles in Table I were prepared from the corresponding nitriles by the general procedure of Fiiiriegan, et al.," as illustrated for 5-[2-(2,6dichloro-3-methylaiiilino)phenyl]tetrazole (14) as follows. A mixture of 2-(2,6-dichloro-3-methyla1iilino)benzoriitrile (9.0 g, 0.0325 mole), Sax3(2.54 g, 0.039 mole), arid NH&l (2.09 g, 0.039 mole) in DlLF (63 ml) was heated, with stirring, at an oil bath temperatiire of 157" for 17 hr. The 1 I N F was removed under reduced pressure aiid the residiie was suspeiided iri cold 1120 (300 nil) which was acidified to pH 2 with concentrated IICl (beware of any liberated HN,). The solid product was collected aiid recrystallized from aqueoiis lIeOH (Sorit) to give 14 (8.6 g, 82.77,) as yellow needles: mp 207-208.5' dec; LIV maxima (9.55; EtOH, 0.01 in HCl), 280 mp (e 7.510), 329 mp (e 7360). .5-[2-(3-Trifluoromethylaniliiio)pheiiyl] tetrazole (4), mp 20520io,had iiv maxima (95('; EtOH, 0.01 -Y iii HCl), 287 mp ( E 16j200)j 336 mp ( e i300). Alternative Preparation of 5-[2-(3-Trifluoromethylanilino)phenyl] tetrazole (4).--A solution of 5-( 2-bromophenyl)tetrazole27 (3.0 g, 0.0222 mole) in dry hexamethylphosphoramide (20 ml) was added slowly to a cooled (ice-water), stirred suspension of S a H (1.80 g of a 5 9 . 4 5 S a H dispersion in mineral oil, 0.0446 mole of NaH) in hesamethylphosphoramide (20 ml). When the vigorous evolution of H, had ceased, 3-trifluoromethylaniline (3.58 g, 0.022% mole) was added to the reaction mixture. The temperature of the mixture was dowly raised under N2. At aboiit 120' a further gaseoiis evolution occurred. When this reaction had subsided, the mixture was then heated a t 185" for l..i hr. The cooled reaction mixture was diluted (cold H&, 400 rnl). The resulting solution was acidified to pH 2 with colicelitrated HC1. The acidified mixture was extracted (CHC13, f o i i r 100-ml portions). The combined extracts were washed (cold € 1 2 0 , 100 ml). The CHC1, soliition was then extracted with 10:; aqueoiis S a O f I (two 30-ml portioiis). The combiiied NaOII A\-
(27) R. A I . Herbst a n d
IC. R. JYilson, J. Oyg. Chem.,
22, 1142 ( 1 9 5 i )
117
extracts were acidified to pH 2 with colicelitrated HC1. The resulting mixture was extracted (CHCI,, four 30-ml portions). The combiiied CIIC13 extracts were washed (HZO, 30 ml), dried (NaZSO,), and filtered, aiid the filtrate was reduced to dryness. The brown oily residue (8.0 g) was purified by chromatography on silicic acid (900 g). The crude product was iiitrodiiced onto the columii in a mixtiire of hIeBCO ( 3 ml) and C ~ H G ( 2 5 ml). The coliimii was eluted with lIe~CO-CsH6 (1 : 20). After the first 400-1nl fraction, the eluate was collected in 300-ml fractions. A buff, cryFtalliiie solid (1.9 g, 28"; yield) was obtained after the removal of the solvent from fractions 2 4 , inclusive. The solid had nip l98-%Wo, with mmp 202-205O wit,h authentic 5-[2-(3trifliioroniethylariilirio)pheiiyl] tetrazole (4). The solid was recrystallized from aqueous EtOH to give b\iU crystals, mp 203-207° (ir spectrum identical with aiitheiitic 4). -4 repeat of the above reaction using 3-(2-~hloropheiiyl)tetraxole27 in place of the 5-(2-bromopheriyl)tetrazole gave 4 iii 34.5"; yield. -2 repeat using .5-(2-chloropheiiyl jtetrazole (0.0222 mole), S a H (0.0666 mole), arid 3-trifluoromethylariiliiie (0.0444 mole) gave 4 iii 46% yield. 1-Methyl-5- [2-(3-trifluoromethylanilino)phenyl] tetrazole (XVIII) and 2-Methyl-5-[2-(3-trifluoromethylanilino)phenyl] tetrazole (XIX).-A cooled (ice-water bath) suspension of 5-[2(3-trifluoromethylanilirio)phe1iyl]tetrazole (10.0 g) in Et& ( 100 mlj was treated with aii ethereal solution of excess CH2NB. Excess CH2N2 and Et& were removed. Fractional recrystallization of the residue from 3IeOH gave two products. The first product (9.4 g) was recrystallized from NeOH to give colorless crystals of SIX, mp ll9.3-121", iimr peak (CL)cl,) at 6 4.3Y (3 H singlet, CH&30 iv
2
,>p-Pregnan-2OO-one
>20 iv
:i 3a,20a-Di hydroxy-5p-pregiiaiie
(7.0 iv)
(>40 ip)
( 2 . 3 iv), 2 . 3 iv
1.1Biv
4
>
Alin leliial dose. mx- 'ke" -
Rat
Mouse
Solvents; notes
40-30 mg, ataxia, sedatioii Poor soly limits study of higher doses Ataxia, coiivulsioii, ( 7 . 0 iv) 1>40 ip) irreg respiratioii Coiivulsions, tremor, (10 iv). sedatioii in 3-12 mg/kg iv (20 iv), 66 =t10 27.3 =t 2 . 4 Jerks, tremor, dyspnea at .;-lo mg ivc ivc iii
6
&-I Iydroxy-.iP-pregiiaii-20-oiie
7
acetate .iB-Pregriaiie-3,20-~ioiie
S
Sa, lia-l>ihydroxy-.jp-pi egiiaii-20-
+
+
811-320 ip 200, (10-20 iv), .i6 iv 160-320
28 ip 60," (9 iv), 9 iv 320 ip, >40 iv
one 9
1)AISO
Corii nil
220 ip
3a-Hydrosy-3p-pl'egiiaiie-ll,20-dioiie20A,
