Org. 1597

Studies in the Steroid Group. Part LXX1X.t Preparation of 2-Aza- 3-0X0, 3-Aza-2-oxo-, '11 6-Aza-17-sxo-, and 4 7-Aza-I&oxo-5a-androstane, and of 3-Aza-2-oxo-5er-chdestane

By Sir Ewart R. H. Jones, 6. D. Meakins,' and K. Z. Tuba, Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY

The steroids named in the title have been prepared by routes in which the yields a t al l stages are higher than 70%. For the ring-A lactams the key stages involve ring opening of 3-oxa- and 3-aza-2,4-diones ; attack by nucleophiles occurs selectively a t position 4. 17-Aza-5a-androstan-l6-one is readily obtained by Beckmann rearrangement of the 16-hydroxyimino-I 7-ketone to 17-aza-D-homo-5cr-androstane-l6,1 -/a-dione, followed by Hofmann degradation. The 1 6-aza-I 7-oxo-isomer w a s prepared from the 17-ketone in six stages by a sequence similar to that used previously for other 1 6-azasteroids.

ALTHOUGH there is now considerable interest in the total synthesis of azasteroids,l most of these compounds, especially the fully reduced ones, have been obtained by introducing the nitrogen substituent into a steroid nucleus. Generally a steroidal ketone is used, and gives an azasteroid in which the nitrogen is at the position

t Part LXXVIII, J. RI. Evans, G. D. Meakins, Y . Morisawa, and P. D. Woodgate, J . Chem. SOC. (C), 1968, 2841.

See, inter aZia, R. van Hes, U. K. Pandit, and H. 0. Huis- man, Rec. Trav. chim., 1967, 86, 1255; E. C. Taylor and Y. Shvo, J . Org. Chem., 1968, 33, 1719; A. J. Meyers and J. S. Sincan, Tetrahedron, 1967, 23, 786.

originally occupied by the carbonyl group or at a contiguous position. Azahomo-compounds are readily prepared by Beckmann rearrangement of ~ x i r n e s , ~ , ~ but formation of ' true ' azasteroids requires loss of one of the skeletal carbons. This is often accomplished by converting the ketone into a suitable mono-derivative of the corresponding seco-diacid ; degradation (Curtius or Hofmann) then affords an amino-acid which is cyclised

2 C. W. Shoppee, R. E. Lack, and S. K. Roy, J . Chem. SOC.,

S . Rakhit and M. Gut, J . Org. Chenz., 1964,29, 859; Steroids, 1963, 3767.

1964, 4, 291.

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1598 J. Chem. SOC. (C), 1969 to a l a ~ t a m . ~ ~ ~ Alternatively a nor-ketone, prepared from the diacid, is subjected to a Schmidt reaction, or the derived oxime to a Beckmann rearrangement.6 The novel preparation of 17-azasteroids by Rakhit and Guts illustrates a different approach: here a

(u) ~;R~.C,H,O 93% b;R2=Ph 95%

iii 1

(Iv)a; 01% (V) a; 05% (TI) aj 95 % b; 85% b; 90%

v i i I

H vi i i H H

H H

(X)a; 90% (X I) a ;73% SCHEME 1

a ; R1= H. b ; R1 = CsH,,

Reagents : i, R2CHO-NaOH-MeOH ; ii, H,O,-KOH-EtOH; iii, C,H,,~N:C:NC,H,,-dioxan; iv, NH,-PhMe, 20" ; v, CH,N,; vi, NaOMe-MeOH ; vii, NaOMe-MeOH-Br,, 20" then reflux; viii, NaOH-H,O-MeOH, then HC1 aq.

substituted carbamic acid, generated during hydrolysis, provides the means of losing carbon.

For other work we required gram quantities of ring-A and ring-D lactams free from other functional groups.

C. W. Shoppee, R. W. Killick, and G. Kriiger, J . Chem. Soc., 1962, 2275.

R. W. Kierstead, A. Faraone, and A. Boris, J . Medicin. Chern., 1967, 10, 177.

N. J. Doorenbos and R. E. Havranek, J . Org. Chem., 1965, 30, 2474.

M. Minssen and J. Jacques, Bull. Soc. chim. France, 1965, m1 11.

The present study was aimed at developing efficient preparations of the compounds named in the title. (None of these appears to have been characterised, although 3-aza-5a-cholestan-2-one and 2-aza-5a-choles- tan-3-one have been reported as an inseparable mixture.6) Reactions in ring A, together with the yields obtained (all over 70%) are shown in Scheme 1 : much of the work is unexceptional, and the detailed nature of the Scheme obviates the need for lengthy discussion.

and b s, by chromic oxidation of a 3p-alcohol or a 3-ketone are less satisfactory; oxidation of 2-hydroxymethylene- 3-ketones with ozoneg or alkaline peroxide1* has been used effectively in other series. The key reactions in Scheme 1 are the formation and selective ring opening of the 7-membered ring anhydrides (IVa and b) and the imide (VIIa). It was already known l1 that when the cholestane anhydride is heated with ammonia it gives one monoacid monoamide predominantly, and the milder conditions used here appear to enhance this effect slightly. A satisfactory procedure for the final stages, ring closure of the monoester monoamides (VIa and b and Xa) was developed only after considerable experi- mentation: here the relative amounts of the reactants and their mode of employment are of critical import- ance.

It is not possible to predict, a priori, that opening of the 7-membered rings should occur by attack at C-4 rather than at C-2. Formulation (Vb) for the cholest- ane acid amide was based on good evidence,ll but in- dependent structural proof for the androstane deriv- atives in Scheme 1 was desirable. Spectrometric ex- amination of the intermediates was not helpful: for example , the low solubility of some compounds hampered n.m.r. study, and with others, such as the ester amides, (VIa and Xa), the spectra did not allow particular structures to be assigned to the isomers. Fortunately, a clear distinction between the 3-aza-2-0x0- and 2-aza- 3-0x0-compounds was made from their n.m.r. and mass spectra (see following paper), and this establishes the structures of the intermediates leading to them.

The surprisingly high degree of selectivity in the ring openings cannot be ascribed to steric hindrance in the

Previous preparations of the seco-diacids (IIIa

general sense, since there appears to be little difference in the ease of access to positions 2 and 4. It may be

* D. J. Hampson, G. D. Meakins, and D. J. Morris, J . Ckern. Soc. (C) , 1966, 1277.

P. Roffey, P. K. Grant, and F. Sondheimer, Tetrahedron Letters, 1967, 1773.

lo K. D. Bingham, W. R. T. Cottrell, and G. D. Meakins, J . Chem. Soc., 1969, 674.

l1 S. Hara, Y . Ike, and N. Matsumoto, J . Pharm. Soc. Japan, 1966, 86, 444.

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Org. 1599 that the cyclic compounds react in a conformation, possibly that depicted (A), such that intermediates formed at C-2 and C-4 differ appreciably in their non- bonded interactions : that arising from attack at

0

i i i (75 % y i e l d ) \liv

(XV) 75% (XVI)78% 9 (XVII)85% vi yield)

90%

SCHEME 2 Reagents : i, KOBut-C,Hl,ONO ; ii, H,SO,-AcOH-H,O ; iii,

SOCI,; iv, NaOMe-MeOH-Br,, 20' then reflux; v, KOH-1,- MeOH-H,O, Z O O , then KOH-MeOH, reflux; vi, CH,N,; vii, NaOMe-MeOH ; viii, K,CO,-MeOH-H,O ; ix, (COC1) ,-C,H, ; x, NH,-Et,O; xi, NaN3-Me,CO-H,0, then reflux in C,H,; xii, ~,~,,*N~~~N*~,H,,-d~oxan ; xiii, NH3-PhMe, 20".

position 2 of the form shown would involve the 13-methyl group in a marked repulsive interaction.

la L. A. Freiberg, J . Amer. Chem. Soc., 1967, $9, 5297. l3 R. Tschesche and A. Hagedorn, Ber., 1935, 68, 1412. l4 D. Varech and J. Jacques, Bull. SOC. chim. France, 1965, 67.

R. D. Heard, M. T. Ryan, and H. I. Bolker, J . Org. Chem., 1969, 24, 172.

Scheme 2 portrays work in ring D. 17-Aza-5a- androstan-3-one (XVII) is readily obtained by the three stages (overall 48%) shown at the top. The more pedestrian route to the 16-aza-17-oxo-isomer (XX) follows closely that used for 3p-hydroxy-17-aza-androst- 5-en-16-0ne,~ and is of such a nature as to establish the structures of the intermediates and the product. [Partial hydrolysis of the diester (XVIII) is the crucial stage in this respect. The structures of the ring-D lactams can be deduced independently, by spectro- metric examination.] Oxidation of cyclic ketones with iodine and base is a complex reaction; l2 to obtain the diacid (XV) l3 in this way requires careful control of conditions.

The convenient preparation of the 17-aza-steroid emerged during attempts to shorten the synthesis of the 16-aza-compound. Hofmann degradation of the ester amide (XIX) gave, unexpectedly, the 17-aza-isomer (XVII). This suggested a mechanism involving the imide (XIV) as an intermediate (Scheme 3).

(XVII) -[Y' CO,Me

SCHEME 3

The realisation that both ester amides (XIX and XXVII) should give the imide (XIV) and thence the 17-aza-compound led to the route shown at the bottom of Scheme 2. [Ring opening of the anhydride (XXIV) is not selective, the acid amides (XXV) and (XXVI) being formed in comparable amounts. From naive considerations of general ' steric hindrance ', ring opening would be expected to be less selective with the 2,3-an- hydrides (IV) in Scheme 1 than with the ring-D system. Hindrance to approach eer se is clearly not the important factor .]

It appeared possible that the imide (XIV) could be obtained more directly via the hydroxyimino-ketone (XIII).14 A confusing situation arising from work on acetylating the 3P-hydr0xy-~~ and 3 p-hydr0xy-111~- derivatives 1 6 9 1 7 of (XIII) was clarified by Hassner and Pomerantz.lS Acetylation proceeds normally, but the oxime acetates are very easily transformed into cyano- acids [ie. 3-substituted derivatives of the acid corre- sponding to the cyano-chloride (XVI)]. The reported conversion l 7 of the 3@-acetoxy-A5-derivative of (XIII)

F. H. Stodola, K. C , Kendall, and B. F. McKenzie, J . Urg.

l7 B. M. Regan and F. N. Hayes, J . Amer. Chem. SOC., 1956,

l8 A. Hassner and J. H. Pomerantz, J . Org. Chem., 1962, 27,

Chem., 1941, 6, 841.

78, 639.

1760.

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1600 J. Chem. SOC. (C), 1969

with thionyl chloride into a cyclic imide [as (XIV)] was questioned by the later workers,lg who considered that the starting material used was, in fact, the corre- sponding cyano-acid ; the authentic cyano-acid does give the 3p-acetoxy-A5-imide.lg Thus, before the present work, compounds containing the hydroxyimino-ketone system had not been treated witn thionyl chloride.

With freshly purified thionyl chloride the hydroxy- imino-ketone (XIII) affords the cyano-chloride (XVI) with a small amount of the imide (XIV). Repetition of the experiment using the same batch of reagent which had been stored carefully for six months, gave the imide as the main product (68%) and only ca. 15% of the cyano-chloride," suggesting that acidic contaminants favour imide formation. This capricious reaction is avoided by the simple preparation of the imide under conditions (see Scheme) employed for converting y-cyano-acids into glutarimides.19

EXPERIMENTAL

For general directions see ref. 20. Experimental pro- cedures are described fully only where they are first men- tioned ; the numbering of the experiments facilitates reference to these operations. In cases where only small quantities of products were further purified (to give ana- lytical specimens), examination by t.1.c. and, where possible, g.1.c. showed that none of the bulk products contained more than ca. 3% of impurities.

3-Aza-2-oxo-compounds (IX) from 3-Ketones (I) .-Ex- periment 1. Furfuraldehyde (freshly distilled ; 5.7 g.) was added during 20 min. to a solution of 5a-androstan- 3-one (la) (15 g.) in MeOH (450 m1.)-H20 (150 ml.) con- taining NaOH (1.5 g.), which was stirred at 45" under N,. After a further 10 min. a t 45" and 3 hr. a t 20", 2-furfuryZ- idene-5a-androstan-3-one (IIa) was filtered off and dried (18-1 g., m.p. 99-103"), m.p. 107-108" (from MeOH), [a], -225" (c 0.9), vmx. 1681 cm.-l (Found: C, 81-8; H, 9.4. C24H32O2 requires C, 81-8; H, 9.1%).

Benzaldehyde (10 ml.) and 5a-cholestan-3-one (5 g.) gave the benzylidene-ketone (IIb) (5.8 g., m.p. 136-140") m.p. 146-147" (from EtOH), [a], -109" (G 1-8), v,,,. 1678 cmrl (Found: C, 86.2; H, 10.3. C,,H,,O requires C, 86-4; H,

Expt. 2. 30% H,O, (150 mI.) and 10% aq. NaOH (300 ml.) were added separately but simultaneously during 10 min. to the ketone (IIa) (17.5 g.) in EtOH (470 ml.). The solution was boiled under reflux for 10 min., and more H202 (150 ml.) and NaOH (300 ml.) were added. The cooled solution was diluted with H,O (600 ml.), acidi- fied with ~ N - H C ~ , and extracted with Et,O. The extract was washed with water and extracted with ~ N - N ~ O H . Acidification of the alkaline layer, extraction with ether, concentration of the dried extract to 50 ml., and cooling to 0" gave the diacid (IIIa) (12.1 g., m.p. 226-230"), m.p. 237-238" (from Et,O) (lit.,7 236-238"), [a], -5" (c 0.8 in EtOH).

10.2Y0).

* This result was obtained after the preliminary announce-

lS T. Kametani, W. Taub, and D. Ginsberg, BUZZ. Chem. SOC.

ment of our work in Chern. Cocnm., 1968, 210.

Japan, 1955, 31, 867.

Oxidation of ketone (IIb) afforded the diacid (IIIb) (3-67 g., m.p. 190-193"), m.p. 197-198" (from Et,O- pentane), identical with authentic material.*

Solutions of the diacid (IIIa) (10 g.) and of NN'-dicyclohexylcarbodi-imide (6.7 g.) in dry dioxan (90 and 20 ml., respectively) were mixed a t 20". After 4 hr., removal of the precipitated dicyclohexylurea, evaporation, and crystallisation from Et,O-light petroleum gave 2,3-~eco- 5a-andvostane-2,3-dioic anhydride (IVa) (7.64 g.), m.p. 124-125", vwx. 1809 and 1760 cm.-1 (Found: C, 74.8; H, 9.4. C,,H,,O, requires C, 75.0; H, 9.3%).

Diacid (IIIb) (3 g.) and the di-imide (1.7 g.) afforded the acid anhydride (IVb) (2.57 g.) , m.p. 140-141" (lit.,11 139-140"), vmX. 1797 and 1752 cm.-l.

A solution of the anhydride (IVa) (7.5 g.) in dry PhMe (90 ml.) was saturated with dry NH, a t 20". After 2 hr. it was evaporated at 60°/15 mm., and the residue was triturated with Et20 to give 3-carbamoyl-2,3-seco-~-nor- 5a-androstan-2-oic acid (Va) (6-6 g., m.p. 245-249"), m.p. 252-254" (from MeOH), vmax. (Nujol) 3420, 3250, 1695, and 1630 cm.-l (Found: C, 71.2; H, 9.5; N, 4.3. C,,H,,NO, requires C, 71.0; H, 9.65; N, 4.4%).

The anhydride (IVb) (2 g.) gave the amide acid (Vb) (1.76 g., m.p. 250-255), m.p. 260-263" (from MeOH) (1it.,l1 263-265") (Found: C, 74.25; H, 11.1; N, 3.0. Calc. for C,,H,,NO,: C, 74.8; H, 10.9; N, 3.2%).

An excess of diazomethane in Et,O was added dropwisc to a stirred suspension of the amide acid (Va) (6 g.) in Et,O (150 m1.)-MeOH (17 ml.) a t 20" until no insoluble material remained and the yellow colour persisted for 15 min. Evaporation and trituration with Et20 (15 ml.) gave methyl 3-carbamoyl-2,3-seco-~-nor-5a-androstan- '2-oate (VIa) (6 g.), m.p. 145-146", [a], +16" (G 0.5), v,, 3502, 3390, 1721, and 1693 cm:l (Found: C, 71.4; H, 9.7; N, 4.3. C,,H,,NO, requires C, 71.6; H, 9.9; N, 4.2%).

The amide acid (Vb) (1-5 g.) afforded the amide ester (VIb) (1.4 g.), m.p. 169-170" (1it.,l1 169-170"), [a], 3-46' (c 0.8) (Found: C, 75-0; H, 10.9; N, 3.0. Calc. for C,,H,,N03: C, 75.1; H, 11.0; N, 3.1%).

Expt. 6. Solutions prepared from Na (2.64 g . ) and MeOH (40 ml.) and from Br, (2.5 ml.) and methanol (10 ml.) were added separately but simultaneously during 20 min. to a stirred solution of the amide ester (VIa) (5.5 g.) in MeOH (55 ml.) a t 20". The solution was boiled under reflux for 20 min., poured into H,O (150 ml.), and extracted with Et,O. The extract was washed (H,O, aq. KHCO,, H,O), dried, and evaporated. Crystallisation from acetone gave 3-aza-5a-androstan-2-one (IXa) (3.1 g.), m.p. 204-206", [a], +52" (c 0.8), vmax. 3409 and 1670 cm.-1 (Found: C, 78-2; H, 10.8; N, 5.0. C18H,,N0 requires C, 78.5; H, 10.6; N, 5-176).

The amide ester (VIb) (1 g.) afforded 3-aza-5a-cholestan- 2-one (IXb) (0-62 g. after crystallisation from Me,CO), m.p. 217-219", [a], +57" (c 0.4), vmx. 3412 and 1670 cm.-l (Found: C, 80.4; H, 11.5; N, 3.8. C,,H,,NO requires C, 80-6; H, 11.6; N, 3.6%). 2-Aza-5a-androstan-3-one (XIa) .-Exfit. 7. The amide

ester (VIa) (2 8.) was dissolved in a solution prepared from Na (0-137 g.) and MeOH (25 ml.), and the solution was boiled under reflux for 5 min. After complete removal of solvent a t 50"/15 mm., the residue was shaken with H,O

Expt. 3.

Expt. 4.

Expt. 5.

20 C. W. Davey, E. L. McGinnis, J. M. McKeown, G. D. Meakins, M. 3 , . Pemberton, and R. N. Young, J . Chem. SOG. (C), 1968, 2674.

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Org. 1601

and acidified with ~ N - H C ~ . Extraction with Et,O gave 3-aza-~-homo-5a-androstane-2,4-dione (VIIa) (1.58 g. after crystallisation from MeOH), m.p. 226-227", [a], + 176" (e 0.5 in EtOH), vmax. (Nujol) 3219, 3100, 1700, and 1665 cm.-l (Found: C, 75.1; H, 9.5; N, 4.7%; M, 303. ClgH,,NO, requires C, 75.2; H, 9.6; N, 4.6%; M , 303).

Expt. 8. A solution of the imide (VIIa) (1.3 g.) in MeOH (80 ml.).-2% aqueous NaOH (32 ml.) was boiled under reflux for 10 min., concentrated to about 25 ml., poured into H,O, and acidified with ~ N - H C ~ . The insoluble material gave 1 -carbamoyl- 1,2-seco-~-nor-5a-androstan-2- ozc acid (VIIIa) (1.17 g.), m.p. 236-238' (from MeOH), [a], +12" (e 0.7 in EtOH), v,, (Nujol) 3440, 3330, 3223, 1725, 1655, and 1595 cm.-l (Found: C, 71.2; H, 9.5; N, 4.5. C1gH,lNO, requires C, 71.0; H, 9-65; N, 4.4%).

Expt. 9. Treatment of the amide acid (VIIIa) (1 g.) with diazomethane as in expt. 5 afforded methyl l-carb- amoy~-l,2-seco-~-nor-5a-androstan-2-oate (xa) (0.95 g.), m.p. 135-136", [a], 0" (G 0-S), v,, 3500, 3380, 1722, and 1693 cm.-l (Found: C, 71.4; H, 9.8; N, 4.35%).

The amide ester (Xa) (0.8 g.), treated as in expt. 6, afforded 2-aza-5a-androstan-3-one (XIa) (0.47 g. after crystallisation from acetone), m.p. 225-227", [a], +24" (c 0-9), vmax. 3410, 3200, and 1675 cm.-l (Found: C, 78.3; H, 10.2; N, 5.2%).

17-Aza-5a-androstan- 16-one (XVII) via the Hydroxy- imino-ketone (XIII) .-Expt. 11. 5a-Androstan-17-one (XII) (3 g.) was stirred under N, a t 20" for 1 hr. with a solution prepared from K (0.99 g.) and ButOH (94 ml.). 3-Methyl- butyl nitrite (3 ml.) was added during 7 min., and the mixture was stirred for 13 hr. More nitrite (1.5 ml.) was added and the stirring was continued for 2 hr. The addition of H,O (70 ml.), acidification with glacial AcOH, and extraction with Et,O afforded the hydroxyimino-ketone (XIII) (2.5 g. after crystallisation from EtOH), m.p. 186- 188" (decomp.) [lit.,14 260" (decomp.)], vmx. 3560, 3290 (becoming weaker on dilution), and 1750 cm.-l.

Expt. 12. A solution of the hydroxyimino-ketone (XIII) (300 mg.) in glacial AcOH (7-2 m1.)-H,O (1-1 m1.)- H,S04 (2 ml.) was heated a t 100" for 1.5 hr. Dilution with water and extraction with CH2C1, afforded 17-am-D-homo- 5a-androstan-16,17a-dione (XIV) (228 mg. after crystall- isation from MeOH), m.p. 203-204", [a], -59" (c O - S ) , vmax. 3376, 1733, and 1712 cm.-l (Found: C, 75.2; H, 9-4; N, 4.5% ; M , 303).

The imide (500 mg.), treated as in expt. 6, gave 17-aza-5a-androstan- 16-one (XVII) (387 mg. after crystallisation from Me,CO), m.p. 256-257", [a], - 18" (c 0.5), vmaXa 3420, 3200, 1720, and 1697 cm:l (Found: C, 78.4; H, 10.1; N, 5.3%).

Expt. 14. A solution of the hydroxyimino-ketone (XIII) (250 mg.) in SOCl, (4 ml. : purified immediately before use by distillations from quinoline and from raw linseed oil) was kept at 0" for 2 hr., and then a t 20" for 5-5 hr. After evaporation under N, a t 20"/15 mm., the residue was dissolved in CH,Cl,, washed with H,O, aq. NaHCO,, and brine, and dried. Evaporation, and crystallisation from hexane gave the imide (12 mg.), m.p. and mixed m.p. 201-203". The material obtained by concentrating the mother liquor was crystallised from hexane to give 15-cyano- 15,16-seco-~-nor-5a-androstan- 16-oyl chloride (XVI) (207 mg.), m.p. 113-115", [a], +15" (c 1-1), vWx 2245, 1787, and 1775 cm:l (Found: C, 71-15; H, 8-85; N, 4.3. Cl,H,,CINO requires C, 70-9; H, 8.8; N, 4.35%). The same batch of SOCl,, used after 6 months in the dark in a

Exfit. 10.

Expt. 13.

stoppered flask, gave the imide (170 mg.) and the cyano- chloride (41 mg.).

Treatment of the cyano-chloride (100 mg.) as in expt. 12 afforded the imide (71 mg.).

17-Aza-5a-androstan-16-one (XVII) via the Amide Ester (XIX).-Expt. 15. Solutions of I, (21-2 g.) in MeOH (400 ml.) and of KOH (15-7 g.) in MeOH (200 m1.)-H,O (200 ml.) were added separately but simultaneously during 6 hr. to a vigorously stirred solution of 5a-androstan-17-one ( 5 g.) in MeOH (900 ml.) at 20". Stirring was continued for a further 12 hr., and the solution was then concentrated to 400 ml. a t 50"/15 mm. After dilution with ice and H,O, acidification with ~ N - H C ~ , and extraction with Et,O, the extract was washed with aqueous Na,S,O,. The pro- duct (6.5 g.) was dissolved in MeOH (90 m1.)-H20 (10 ml.) containing KOH (6-5 g.), and the solution was boiled under reflux for 4 hr., then cooled. The sparingly soluble K salt was collected, washed with MeOH, and boiled with H,O (500 ml.) and a little charcoal. Filtration and cooling to 5", followed by the addition of ~ N - H C ~ precipitated the diacid (XV) (4.4 g. after crystallisation from MeOH), m.p. 255-257" (lit.,13 253-254"), [a], -18.5" (c 0.5 in EtOH), vmx. (Nujol) 1705 crn.-l (Found: C, 70.8; H, 9.3. Calc. for ClgH3004: C, 70.8; H, 9.4%).

Treatment of the diacid (4 g.) with diazomethane as in expt. 5 afforded dimethyl 16,17-seco-5a-androstane-16,17- dioate (XVIII) (3-62 g.) as an oil, [a], -22" (c O - S ) , vmx 1745 and 1730 cmrl (Found: C, 71.8; H, 9.6. C,lH,40, requires C, 72.0; H, 9.7%).

A solution of the diester (XVIII) (3 g.) in MeOH (60 ml.) was boiled under reflux for 6 hr. with K,CO, (3-5 g.) in H 2 0 (15 ml.). Concentration, dilution with H,O, washing with Et,O, acidification, and extraction with Et,O gave 13a-methoxycarbonyl- 13,16-seco-~-nor-5a- androstan-16-oic acid (XXI) (2-1 g.), m.p. 128-130" (from Et,O-hexane), [a], -33" (c 0.9 in EtOH), vmax 1730 and 1708 cm.-l (Found: C, 71.1; H, 9.5. C,OH,,O, requires C, 71.4; H, 9.5%).

Expt. 17. A solution of the ester acid (XXI) (2.4 g.) and oxalyl chloride (3.5 ml.) was stirred a t 68" for 1.5 hr., more oxalyl chloride (1 ml.) was added, and stirring was continued for 30 min. Evaporation a t 60", finally a t 2 mm., gave the ester-chloride (XXII) (2.4 g.), vmax 1785 and 1733 cm.-l. A solution of this material in dry Et,O (150 ml.) was saturated with NH, a t 20". After 1 hr. isolation with ether gave methyl 15-carbamoyl-l5,16-seco-D-nor-5a- androstan-16-oate (XIX) (2.1 g.), m.p. 148-150" (from ether), [a], -36" (G 0.9 in EtOH), vmX. 3510, 3380, 1722, and 1695 cm.-l (Found: C, 71.8; H, 9.6; N, 4.2%).

Treatment of this compound (1.6 g.) as in expt. 6 gave the 17-aza-compound (XVII) (1.06 g.). 17-Axa-5a-androstan-16-one (XX) via the Anhydride

(XXIV).-Expt. 18. The diacid (XV) (5 g.), treated as in expt. 3, gave 16,17-seco-5a-androstane-16,17-dio~c anhydride (XXIV) (4.24 g . after crystallisation from Et,O-light petroleum), m.p. 184-186", v,, 1810 and 1765 cm.-l (Found: C, 74.9; H, 9.0%). This compound (2 g.), as in expt. 4, afforded a mixture (1-92 g., m.p. 196-204") of the amide acids (XXV and XXVI). [Repeated crystall- isation from EtOH yielded 15-carbamoyl-15,16-seco-~-nor- 5a-androstan-16-oic acid (XXV) (0-71 g.), m.p. 228-229", Y,, (Nujol) 3440, 3310, 3200, 1700, and 1652 cm.-l (Found: C, 71.7; H, 9-5; N, 4.5%). Esterification, as in expt. 5, gave the amide-ester (XIX) (97%).] Treatment of the mixture (1 g.) with diazomethane afforded the amide

Expt. 16.

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1602 J. Chem. SOC. (C), 1969

esters (XIX and XXVII) (1.01 g.), vmx 1720 and 1696 cm,-l. When treated as in expt. 6, the mixture of amide esters (1 g.) afforded the 17-aza-compound (XVII) (0.62 g.). Another sample of the mixture (1 g.) gave, as in expt. 7, the imide (XIV) (0.88 g.).

16-Aza-5a-androstan-17-0ne (XX) .-Expt. 19. A solution of NaN, (2 g.) in H,O (7 ml.) was added during 15 min. to a vigorously stirred solution of the ester chloride (XXII) (2-2 g.) in Me,CO (45 ml.) a t 5O, and stirring was continued for a further 20 min. After dilution with H,O (70 ml.) and extraction with C,H, (100 ml.), the dried extract was concentrated to 50 ml., and boiled under reflux for 1.5 hr. Evaporation afforded methyl 15-~socyanato- 15,16-seco-~-no~-

5ci-and~ostan-16-oate (XXIII) (1.66 g. after crystallisation from hexane), m.p. 72-73", vmx. 2280 and 1730 cm.-l (Found: C, 72.3; H, 9.2; N, 4.2%).

Treatment of the isocyanate (300 mg.) as in expt. 7 (but with a reflux period of 20 min.) afforded 17-aza-5a- adyostan-1 6-one (230 mg. after crystallisation from ace- tone), m.p. 259-260°, vmx. 3451, 3200, 1720, and 1700 cm.-l (Found: C, 78.3; H, 10.25; N, 5.2%).

The award of a United Nations Fellowship (to K. 2. T.) is gratefully acknowledged .

[9/389 Received, ,March 6th, 19691

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