COMMUNICATIONS TO THE EDITOR
3710
VOI. 74
vanadium(II1) ions. The possibility of rapid sepa- and K’ = groups as shown in Table I. These ration-induced exchange brought about when the phthalides can be degraded to phthalic or benzoic reaction mixture is added to alcoholic ala‘-dipyri- acid derivatives to prove the position of the chlorine dyl is not excluded by these observations. Dod- atom as indicated in the previous paper. 4-Chloro-7-methoxy-3-rnethyl-phthalide (111) son’s work with the iron(I1)-iron(II1) exchange showed exchange half-times of the order of 15-50 was prepared from 2-amino-3-methoxyacetopheseconds with the reactant species a t ca. 0.001 f none3by reducing the ketone to the alcohol and reeach. Reduction of the concentrations of the placing the amino by a cyano group. On hydrolyvanadium reactants may slow the observed rapid sis, I1 was formed which was chlorinated to 111 exchange rate to a point where kinetic studies with chlorine in acetic acid or with sodium hypocould be undertaken, but the techniques used so far chlorite and hydrochloric acid. 4-Chloro-3-hydroxy-7-methoxy-3-methylphthahave not permitted this because of difficulties with oxidation of both vanadium species in solutions at lide (V) was prepared by replacement of the amino by cyano in 2-amino-3-methoxyacetophenone, hyhigh dilution by traces of oxygen present. I V and chlorination to V. Both IV and drolysis to DEPARTMENT OF CHEMISTRY UNIVERSITY OF CALIFORNIA ~VILLIAM R. K I N G , J R . 1’probably exist in equilibrium with the correspondLos ANGELES 24, CALIFORNIA CLIFFORD S. GARNER ing o-carboxyacetophenonestructure and both will RECEIVED JUNE 6, 1952 form “normal” esters with diazomethane and “pseudo” esters with acid-methanol or acid chloride-methanol procedures. SYNTHESIS OF DEGRADATION PRODUCTS OF AUREOMYCIN
4-Chloro-7-methoxy-3-methyl-3-phthalidecar-
Sir : The synthesis of several degradation products‘ of Aureomycin by unequivocal methods has been accomplished. In each case these synthetic products were compared with the degradation products by means of m.p., mixed m.p., ultraviolet and infrared absorption spectra, and other properties to prove their identity. PITO.
I1 I11 IV
V VI
VI1 VI11 IX
R
R‘
H
-H
C1
-H
H
-OH -OH
c1
M.p., “C.
73-75 113-14 164-65 204-206
--C
boxylic acid (VII)was prepared by adding hydrogen cyanide to 2-cyano-3-methoxyacetophenone,hydrolysis of the product to VI and chlorination to VII. The compound was resolved by crystallizing ~ (1.2% in the brucine salt from water; [ a ] ” f25” ethanol). 3-(4-Chloro-7-methoxy-3-methylphthalidyl) -succinic acid (IX) was prepared by treating I V with
TABLE1 I1
Theory OCHi
07.4 50.5 61.8 52.4
5.6 4.2 5.2 3.9
H C1 H
-COOH -COOH -CH*COOH
168-70 199-200 207-209.5
59.5 51.5 57.1
4.5 3.5 4.8
c1
-CH&OOH CHnCOOH
209-210.5
51.1
4.0
I
-
CI
16.7 16.0 15.5 13.8 10.5 10.8
7
Found OCHI
C
H
66.9 57.0 62.1 52.3
6.0 4.6 5.9 3.9
59.8 51.7 57.3
5.2 3.9 5.2
51.4
4.4
T
C1
16.3 16.4 15.4 13.8
9.7 10.9
I
CHzCOOH
The first of these products is 6-chloro-3-methoxy- phosphorus pentachloride to form the “pseudo” phthalic anhydride (I) which definitely places the acid chloride which reacted with sodio diethyl carposition of the rnethoxyl and chloro groups in rela- bethoxysuccinate. Hydrolysis and decarboxylation to the other 2 substituents on the benzene ring. tion yielded VI11 which was chlorinated to IX. This compound was prepared from 3-methoxy-6- Two racemates resulted and the higher melting one, chloroanthranilic acid2by replacement of the amino m.p. 228-229’ with gas, was resolved by crystallizgroup by a cyano group through a Sandmeyer re- ing the brucine salt from ethanol; m.p. 209-210.5’ action and hydrolysis to the phthalic acid deriva- with gas; [ c y I z 6 ~- 2 0 . 4 O (5y0in alcohol). tive, m.p. 187-188’. Anal. Calcd. for C9H~04C1: (3) J. C.E. Simpson, el d.,J . Chcm. S O L . 646 (1945). C, 50.8; HI 2.4; C1, 16.7. Found: C, 51.5; H, S. KUSHNER CONTRIBUTION FROM THE JAMES H. BOOTHE 2.7; C1, 16.7. LEDERLELABORATORIES DIVISION JOHNMORTON I1 The remaining compounds are phthalides of the AMERICAN CYANAMID COMPANY JOSEPH PETISI following general formula in which R = chlorine PEARLRIVER, N E W YORK J . H. WILLIAMS RECEIVED JUNE23, 1952
OG
sir:
OCHs
I
11-IX
ol., T E I E J O m N a L . 74, 3710 (1962). (1) E. 1.B d w , rl ol., 1.Or#. C h m . , l?,180 (leS1).
(1) B. L. Htttchbg6,
81
DEGRADATION OF AUREOMYCIN
I n a preliminary report’ certain of the physical and chemical properties of aureomycin were out(1) R. W. Bro-rd, A. C. Dornbuah, S. Gordon, E. L. Hutchias, A. R.Kohl-, 0. Krupka, S,Kushner, D.V. Lcfemine and C.Pidacks. Sckncr, lW,199 (1949).
July 20, 1952
COMMUNICATIONS TO THE EDITOR
371 1
lined. From the analytical data presented an em- microns further suggested the presence of a succinic pirical formula of CzzH~7NzC10scould be calcu- acid moiety. The dibasic acid was postulated to lated. I n the present communication a number of be 4-chloro-7-methoxy-3-methylphthalide-3-sucdegradation products of aureomycin will be de- cinic acid. The synthesis3 of the above compounds unequivscribed. From alkaline fusion of aureomycin 5-chlorosali- ocally prove the assigried structures. cylic acid, dimethylamine and ammonia were obFinally, a second dibasic acid, m.p. 203-204", anal. Calcd. for C1~H1507C1:C, 52.6; H, 4.38; tained. The methylation and subsequent permanganate C1, 10.4; C-CH3, 4.40; OCH3, 9.58. Found: C, oxidation of aureomycin resulted in the formation of 52.3; H, 4.81; C1, 10.5; C-CHp, 4.89; OCHa, a number of 9-chloromethoxybenzene derivatives 9.60, was isolated from the oxidation mixture. which were separated by fractional extraction with The formation of the dimethyl ester, m.p. 108various buffers and by selective crystallization. 109.5", and the anhydride, m.p. 200-201", estabThe simplest oxidation product was identified as lished the presence of two carboxylic acid groups. 6-chloro-3-methoxyphthalic acid, m.p. 186-187", The infrared absorption spectra of the anhydride anal. Calcd. for CgH7C105: C, 46.91; H, 3.06; showed typical bands for glutaric anhydride, in C1, 15.37. Found: C, 47.04; H, 3.57; C1, 16.13. contrast to the bands for succinic anhydride in the The anhydride of this compound melted at 187- previous compound. The ultraviolet absorption spectra of the two dibasic acids were almost identi188". Further fractionation yielded a monobasic acid, cal. The unknown dibasic acid was demethylated m.p. 199-200" (dec.) [cY]*~D+25" (methanol), with hydrobromic acid to the phenolic acid, m.p. anal. Calcd. for CllHOO~Cl:C, 51.5; H, 3.54; 172.5-175', and then oxidized with acid permangaC1, 13.8; OCH3, 12.1; C-CH3, 5.35. Found: C, nate to yield tricarballylic acid. The dibasic acid 51.5; H, 4.02; C1, 13.5; OCH3, 11.9; C-CH3, was, therefore, postulated to be @-(4-chloro-75.18, which readily formed a monomethyl ester, methoxy-3-methylphthalide-3)-glutaricacid. m.p. 96-100". Infrared absorption spectra showed Alkaline fusion of the phthalide derivatives, with the presence of carboxyl, lactone, carbonyl, aroma- the exception of 4-chloro-7-methoxy-3-methyltic unsaturation, terminal methyl and aromatic phthalide, gave 5-chloro-2-methoxybenzoic acid. ether absorption. Decarboxylation resulted in the (3) S. Kushner. J. H. Boothe, J. Morton, J. Petisi and J. H. Wilformation of carbon dioxide (one mole) and a neu- liams, THISJOURNAL, 74, 8710 (1952). tral compound, m.p. 112-113". The latter was B. L. HUTCHINGS identified as 4-chloro-7-methoxy-3-methylphthaC. W. WALLER S.GORDON DIVISION lide, anal. Calcd. for C10Hg03CI: C, 56.5; H, 4.24; LEDERLELABORATORIES CYANAMID COMPANY R. W. BROSCHARD C1, 16.7. Found: C, 56.6; H, 4.5; C1, 16.75. AMERICAN C. F.WOLF Thus, the monobasic acid was 4-chloro-7-meth- PEARLRIVER,NEWYORK A. A. GOLDMAN oxy-3-methylphthalide-3-carboxylic acid. J. H. WILLIAMS When 4-chloro-7-methoxy-3-methylphthalide was RECEIVED JUNE 23, 1962 oxidized with alkaline permanganate, 6-chloro-3methyloxyphthalonic acid or 6-chloro-3-methoxyphthalic acid was obtained, depending on whether the manganese dioxide was filtered off before or afSTEROIDS. XXXV1I.l A TEN STEP CONVERSION ter acidification. The former compound melted at OF PROGESTERONE TO CORTISONE 224-227' (dec.), anal. Calcd. for CloHTO&!l: C, Sir : 46.4; H, 2.71; C1, 13.7. Found: C, 46.8; H, Taking advantage of our recently described2 3.12; C1, 13.9; C-CH3, 0.0. If the oxidation was methods for the introduction of the lla-hydroxy carried out in neutral solution, 3-hydroxy-3-methyl- group into ring C unsubstituted steroids we have 4-chloro-7-methoxyphthalide, m.p. 198-293", anal. started a program directed at the chemical syntheCalcd. for C10H9C104:C, 52.5; H, 3.94; C1, 15.54; sis of the 11a-hydroxy analogs of the various OCH3, 13.6; C-CH3, 6.6. Found: C, 52.65; H, natural hormones; their application to the case 4.47; C1, 15.26; OCH3, 10.36; C-CH3, 6.13, was of 11a-hydroxyprogesterone (I) has already been formed. Methylation of this compound yielded a r e p ~ r t e d . ~ The physical constants of the synthetic normal ester, m.p. 69-70", and a pseudo ester, product proved to be in excellent agreement with m.p. 188-190". those reported by Peterson and Murray' for a subThe oxidation residues further yielded a dibasic stance obtained in 10% yield by the microbiological acid, m.p. 211-212', [ a ] " ~-20.2 (ethanol), anal. oxidation of progesterone with the mold Rhizopus Calcd. for C14H1307C1: C, 51.1; H, 3.96; C1,10.8; arrhizus (their strain R H 176) and assigned the OCH8, 9.45; C-CH3, 4.56. Found: C, 51.1; HI 11a-hydroxyprogesterone structure. 5.54; C1, 10.7; OCH3,9.24; C-CH3, 4.53. Anan(1) Paper XXXVI, J. Romo, G. Rosenkranz and C . Djerassi, J . hydride, m.p. 209-210°, was readily formed when Chcm., in press. the dibasic acid was heated in acetic anhydride. Org. (2) G.Stork, J. Romo, G. Rosenkranz and C . Djerassi, T H X JOUR~ Ultraviolet and infrared absorption spectra indi- NAL, 71,3646 (1951); .C.Djerassi. 0. Mancera, G. Stork and G. Rosencated the presence of the phthalide nucleus in both krnnz. ibid., 78,4496 (1961); C . Djcrad, E. Batrcn, M. Velascoand G. the acid and the anhydride. The typical absorp- Rosenkranz, ibid., 74, 1712 (1952): F. Sondhcimer, R. Yaahin, 0. and C . DjcrPui, ibid., 74, 2698 (1952). tion bands of the latter compound a t 5.3 and 5.6 Rosenkranz (3) 0. Mancera, J. Romo, F. Sondheimer, G. Rosenkrnnr and C . (2) R. Kuhn and K. Dury, Chcm. Bcr., 84,663 (19511, reported the finding of 6-chlorosalicylic acid and dimethylamine but no ammonia in 8 similar experiment on aureomyan.
Djerassi, J . 011. Chcm., 17, in preaa (1962). (4) D. H. Peterson and H. C. Murray, THISJOUENAL. 74, 1871 (1952).
