AN ANTIMALARIAL ALKALOID FROM ... - ACS Publications

B. R. BAKER, ROBERT E. SCHAUB, and JAMES H. WILLIAMS. J. Org. Chem. , 1952, 17 (1), pp 109–115. DOI: 10.1021/jo01135a011. Publication Date: January ...
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A S ANTIMALARIAL ALKALOID FROM HYDRAKGEA. X. SYNTHESIS OF 3-[P-KETO-r-(4-METHYL-8-PYRROLIDYL)PROPYL]-4QUINAZOLONE B. R. BAKER, ROBERT E. SCHAUB,

AND

JAMES H. WILLIAMS

Received September 27, 1961

Two possible structures suggested for the Hydrangea alkaloid contained an hydroxymethylpyrrolidine group in the side chain, one of which was 3-B-keto~-(4-hydroxymethyl-2-pyrrolidyl)propyl]-4-quinazolone (IX, R = OH) (1). It seemed advisable to synthesize the desoxy derivative of this compound (IXa) in order to establish the method employed without the additional complicating factor of the hydroxyl (or methoxyl) group. Application of the modified aminoketone cyclization ( 2 ) to the preparation of l-c:~rbethoxy-4-methylpyrrolidine-2-acetic acid (VIII) would require as an intermediate 3-methyl-4-carbobenzoxyaminobutyric acid (Va), for which a number of methods were investigated. Fteduction of P-cyanobutyric acid should give rise to 4-methyl-2-pyrrolidone which could be hydrolyzed to 3-methyl-4-aminobutyric acid. According to Higginbottom and Lapworth (3) treatment of crotonic ester with sodium cyanide leads to the sodium salt of 3-cyanobutyric acid. These authors then hydrolyzed the intermediate cyano acid, without isolation, to methylsuccinic acid. Attempted isolation of this intermediate has now shown that less than 10% of 3-cyanobutyric acid was left in the solution before addition of alkali. That the P-cyano group is hydrolytically unstable under the conditions of the sodium cyanide reaction is not surprising since 6-cyanopropionic acid has been reported to hydrolyze in water at room temperature a t an appreciable rate (4). Chrtius degradation of p-carbomethoxyisobutyryl chloride (IV), prepared in five steps from methyl crotonate ( 5 ) , by sodium azide and rearrangement in the preaence of benzyl alcohol followed by alkaline hydrolysis, gave the desired butyr,ic acid derivative, T’a. 3-Methyl-4-phthalimidobutyric acid was prepared similarly in poor yield by treatment of the isocyanate with phthalic anhydride. However, this synthesis was long and application to the preparation of the me1 hoxy analog, Vb, would be quite laborious. Another approach investigated was the alkylation of ethyl sodiomalonate with 2-cliloropropylphthalimide (6). KOappreciable reaction took place after 42 hours in boiling tert-butyl alcohol and the chloro compound was recovered unchanged. This difficulty was surmounted by condensation of the easily accessable phthalimidoacetone (Ia) (7) xi-ith ethyl cyanoacetate by the procedure of Cope and coworkers (8) to IIa in 68% yield followed by saturation to IIIa with hydrogen in the presence of platinum oxide catalyst in near quantitative yield. Strong acid hydrolysis with decarboxylation led to 3-methyl-4-aminobutyric acid which was isolated by carbobenzoxylation to Va in 82% yield. Some difficulty was experienced in obtaining 3-methyl-4-carbobenzoxyamino109

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B. R. BAKER, R . E. SCHAUB, AND J. H. WILLIAMS

butyryl chloride, VI. A number of attempts to prepare the acid chloride from Va, characterized as the anilide, at 0-25", were unsuccessful. Since no anilide or starting acid could be obtained, the product was probably a pyrrolidone.' However, when acid chloride formation was carried out with a slight excess of thionyl 0

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C6HsCH2OCNHCHzCHCH2CCH(COOEt)z +VI1

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IX a Series, R = H h Series, R = CHBO

chloride in ether (containing 0.5% of pyridine) a t -25" or -Go,the yields of crystalline anilide, m.p. 131-132", mere 37 and 280/0, respectively. The acid chloride, prepared a t -25", was condensed with magnesiomalonic ester in the usual manner to VI1 in 44% yield. Hydrogenation, hydrolysis, and carbethoxylation afforded the key 2-pyrrolidineacetic acid, VIII, in 42% yield. The side chain was 1 Kanewskaja (9) has observed that 4-benzamidobutyric acid treated with thionyl chloride a t room temperature gave 1-benzoyl-2-pyrrolidone and that a t 0" &lo% acid chloride was formed which was characterized as the amide.

AN ANTIMALARIAL ALKALOID FROM HYDRQNGEA. X

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then completed, condensed with 4-quinazolone, and hydrolyzed to the desired model compound, IXa, as described for similar compounds (2). Condensation of 2-hydroxy-3-methoxypropylchloride with potassium phthalwhich was oximide gave 87-92% of 6-hydroxy-y-methoxypropylphthalimide* idized to 1-methoxy-3-phthalimidoacetone(Ib) in 65% yield with acid dichromate. Condensation with ethyl cyanoacetate gave crystalline IIb in 41% yield which was reduced to IIIb in 82% yield. The synthesis of the desired aikaloidlike structure, IXb, by this process was not completed as the simultaneous work on the synthesis of IXb by the itaconic acid approach described in the following paper was successfully concluded at this time. Acknowledgement: The authors are indebted to Miss E. Sherman for literature searches and Mr. Louis Brancone and his staff for the microanalyses. EXPERIMENTAL

Ethyl R-cyano-J-methyZ-4-phthaZ~m~do-2-butenoa~e (IIa). A mixture of 164 g. of phthalimidoacetone (Ia) (7),25.5 g. of ammonium acetate, 73 cc. of acetic acid, 100 cc. of ethyl cyanoacetate, and 500 cc. of benzene was refluxed under a constant water separator (8) for ten hours when water separation was complete. Washed twice with water, the organic solution was evaporated t o dryness in vacuo. Recrystallization of the residue from 1200 cc. of alcohol gave 162 g. (68%) of tan crystals, m.p. 93-103". This material appeared t o be a mixture of cis and trans isomers since i t gave proper combustion values. It was used in the next step without further purification. When a sample was recrystallized from alcohol a ncaarly pure isomer, m.p. 117-120",was obtained as white crystals. Anal. Calc'd for C16Hl,n'204: C, 64.4;H, 4.70; N , 9.40. Found: C, 64.1;H, 4.82;N,9.80. Ethyl d-cyano-9-methyZ-4-phthalimidobutyrate (IIIa). A hot solution of 162 g. of IIa in 350 cc. of Methyl Cellosolve was stirred with 50 g. of h'orit for ten minutes, filtered, and the Norit washed with 190 cc. of Methyl Cellosolve. The filtrate was shaken with hydrogen at 2-3 atm. in the presence of 0.8 g. of platinum oxide until one mole-equivalent of hydrogen WafIabsorbed (two to three hours). The filtered solution was evaporated t o dryness in uacuo. The residue was dissolved in 400 cc. of ethyl acetate and washed with 120 cc. of 1 N hydrochloric acid, then water. Evaporation of the organic solution in vacuo gave 157 g. (96%) of an amber oil. .4nal. Calc'd for C I ~ " ~ S Z OI,T:,9.31.Found: K,9.46. :?-.%iethy1-~-phthaEimidobut~ric acid. T o a stirred solution of 10.4 g. of sodium azide in 52 cc. of water cooled in an ice-bath was added a solution of 20 g. of methyl 6-methylglutaryl chloride (.5) in 52 cc. of acetone at such a rate that the temperature was 8-10' (ten minutes). After being stirred in the ice-bath for one hour more, the mixture was diluted with 80 cc. of chloroform and SO cc. of ice-water. The separated aqueous layer was extracted with an ndclitional 40 cc. of chloroform and the combined extracts dried over calcium chloride in an ice-bath for three minutes. The chloroform solution was refluxed for 45 minutes when nitrogen evolution was complete. The chloroform was removed in vacuo. The residual isocyanate in 120 cc. of xylene was refluxed with 16.6 g. of phthalic anhydride for three hours when carbon dioxide evolution ceased. This solution n-as processed in a number of ways, the best found being as follows: Two-thirds of the xylene solution was treated with a hot solution of 14.3g. of anthranilic aci(l in 100 cc. of toluene to remove excess phthalic anhydride. The solid and gum which ~

Pearson, Sigal, and Krug (10) have recently described the synthesis of this compound, m.p. 61.5-62.5",by a laborious three-step process from 2-hydroxy-3-methoxypropyl chloride in 14% over-all yield. :!

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B. R. B I K E R , R. E. SCHAUB, S S D J. H. WILLIAMS

separated were rejected. The solution was washed with excess aqueous sodium bicarbonate, then with water. Evaporation in vacuo gave 14.3 g. of an oil. This oil was refluxed with 71 cc. of acetic acid and 71 cc. of 6 N hydrochloric acid for 30minutes, then concentrated almost to dryness in vacuo and diluted with water. The oil was extracted with ethyl acetate which was back-extracted with excess saturated sodium bicarbonate solution. Acidification gave 2.4 g. (13%) of product, m.p. 138-140". Recrystallization from benzene gave nearly white crystals, m.p. 139-140". Bnal. Calc'd for C13H13xOa: C, 63.1; H, 5.25; N, 5.65. Found: C, 63.1; H, 5.44; N , 5.90. 3-il.lethyl-Q-carbobenzoxyaminobutyric acid (Va). (A).A mixture of 64 g. of ethyl 2-cyano3-methyl-4-phthalimidobutyrate(IIIa) and 640 cc. of 6 N hydrochloric acid was refluxed for eight hours when carbon dioxide evolution was essentially complete. Solution was complete in about three hours. The cooled mixture was filtered from phthalic acid and evaporated to dryness in vacuo.The residue of ammonium chloride and 3-methyl-4-aminobut)-ric acid hydrochloride was dissolved in 250 cc. of water and basified with 40.6 g. of sodium hydroxide in 180 cc. of water. The solution was concentrated in vacuo t o remove ammonia until salt separated, then water was added to the original volume. The solution was cooled to 4" in an ice-bath and treated dropwise with stirring with 67 cc. of 70% benzyl chlorocarbonate over a period of seven minutes. The mixture was stirred in the ice-bath for 40 minutes, being maintained a t pH 9-11 by addition of 10% sodium hydroxide as needed (25 cc.). The mixture was washed with ethyl acetate. Acidification of the aqueous layer gave an oil which was extracted with ethyl acetate. The extract, washed with water, was evaporated t o dryness in vacuo leaving 43.8 g. (82%) of an oil which was nearly pure. ilnal. Calc'd for C13HI7NO4: C, 62.2; H, 6.83; N , 5.57. Found: C, 63.2; H, 7.28; N , 5.26. ( B ) .The chloroform solution of azide from 50 g. of methyl P-methylglutaryl chloride, prepared as described in the preceding experiment, was refluxed with 50 cc. of benzyl alcohol for one hour when gas evolution was complete. The solution was evaporated t o dryness an vacuo. The residue was dissolved in 140 cc. of methanol and 163 cc. of 10% sodium hydroxide was added. After 30 minutes the solution was diluted with 415 cc. of water and washed with ethyl acetate. The aqueous layer was acidified, extracted with ethyl acetate, and the extract evaporated t o dryness in vacuo. The residue still contained some benzyl alcohol. It was dissolved in 200 cc. of 57, sodium hydroxide and washed ta-ice with carbon tetrachloride. Acidification gave an oil a hich was isolated by ethyl acetate extraction; yield, 24.5 g. (397,). Anal. Found: K, 5.87. (C). A mixture of 2.4 g. of 3-methyl-4-phthalimidobutyricacid and 0.55 g. of anhydrous sodium carbonate in water was heated to complete solution, then treated with hydrazine, hydrochloric acid, alkali, and benzyl chlorocarbonate according to the procedure employed for 3-methoxy-5-carbobenzoxyaminovalericacid (11) ;yield, 0.SO g.(33%) of an oil. 3-Methyl-4-carbobenzoxyaminobutyryl chloride (VI)and anilide. T o a solution of 620 mg. of the acid, V, in 1.24 cc. of reagent ether (containing 0.5% pyridine) cooled in a Dry Icecarbon tetrachloride bath (-25') was added 0.21 cc. (10% excess) of thionyl chloride. After 30 minutes a t -25' volatile material was removed at -25" i n vacuo.The residual acid chloride was dissolved in 10 cc. of toluene precooled t o -25", then treated with 0 6 c c . of aniline a t such a rate that the temperature did not rise above -15". The reaction mixture was washed with dilute hydrochloric acid and aqueous sodium bicarbonate. Evaporation of the toluene solution i n vacuo gave 630 mg. of semi-solid which was recrystallized from benzene-heptane; yield, 300 mg. (3770), m.p. 131-132". Anal. Calc'd for C I ~ H ~ ~ C, N ~69.9; O ~H: , 6.74; N , 8.59. Found: C, 69.9; H, 7.45; N, 8 51. When the reaction time was increased t o one hour a t -25", the yield of anilide was 367,, indicating the acid chloride is stable at this temperature. At -44" for 30 minutes the yield was 28% while a t 0" or 25' no crystalline anilide could be isolated and no acid %-asrecovered.

.4S -4STIIWALIRIAL ALKALOID FROM HYDRANGEA. X

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Ethyl (3-methyl-4-carbobenzoxyaminobutyryl)maEonate (VII). A solution of 41.6 g. of V in ~83cc. of reagent ether (containing 0.5% pyridine) was cooled in a Dry Ice-acetone bath and treated with 14 cc. of thionyl chloride a t such a rate that the temperature was -30" t o -23". The solution was allowed t o stand one-half hour in a Dry Ice-carbon tetrachloride bal h , then the volatile matter wasremoved in VUCZLO (bath -25"). The residual acid chloride was dissolved in 110 cc. of toluene precooled t o -28'. This solution was kept a t -25" nhilc small amounts were added dropwise from a pipette t o a stirred solution of 37 g. of magnesium methoxide and 79 ec. of ethyl malonate in 160 cc. of toluene at room temperature over a period of one hour. The product was isolated as described for ethyl (5-carbobenzoxyaminovalery1)malonate (11); yield, 26.5 g. (44Gd) of oil i+hich gave :t red ferric chloride test and was nearly pure. Anal. Calc'd for C?oHs7S07:C, 61.1; €1, 6.89; S , 3.57. Found: C, 61.8; H, 7.08; S , 2.53. l-Ca1~bethoxy-~-methylpyrrolidine-2-acetic acid (VIII). A solution of 27 g. of VI1 in 100 cc. of acetic acid was shaken with 8 g. of S o r i t for ten minutes, then filtered, and the Korit washed with 25 cc. of acetic acid. The filtrate was shaken with hydrogen a t 2-3 atm. in the presence of 5 g. of 10% palladium-charcoal. It was necessary to remove the poisoned catalyst and add fresh catalyst before the necessary amount of hydrogen (78 mol-%) was absorbed. Then 0.5 g. of platinium oxide was added. An additional 64 mol-% of hydrogen was absorbed in 16 hours. The filtered solution was evaporated t o dryness i n vacuo. The crude 4-methyl2-pyrrolidinemalonic ester was refluxed with 180 cc. of 6 N hydrochloric acid for two hours, t h m evaporated to dryness in vacuo. The residue was dissolved in 48 cc. of water and 11 g. of sodium hydroxide in 80 cc. of water was added. T o the solution cooled in an ice-bath was added 8.8 cc. of ethyl chlorocarbonate in 35 cc. of toluene dropwise a t such a rate that the temperature was 4-7". rlfter being stirred in the ice-bath an additional 40 minutes, the alkaline layer was separated and acidified. The product was isolated by three 150-cc. extractions with chloroform; yield, 6.8 g. (42%). Anal. Calc'd for CIOHI7NO~: N, 6.51. Found: ?;,6.36. The anilide was obtained as an oil via the acid chloride. Anal. Calc'd for ClBHd203: N, 7.58. Found: N, 7.62. J-[~-Keto-y-(l-carl;refhoxy-/t-methyl-d-pyr~olidyl)propyl]-~-quinazolone. The acid, VIII, (5.6 g.) was converted t o the acid chloride, diazoketone, and bromoketone as described for l-carbethoxy-4-methoxy-2-piperidylacetic acid (2) ; yield, 3.6 g. (48%) of oily bromokei one which was condensed with 1.6 g . of 4-quinazolone to give a 30% yield of crystalline product from benzene-heptane, m.p. 121-123'. Recrystallization from the same solvents afforded white crystals, m.p. 123-124". Anal. Calc'd for C19H23Na0,:C, 63.9; H, 6.45; ?;,11.7. Found: C, 63.8; H, 6.92; W, 11.5. When the diazomethane reaction was allowed to proceed for only one hour (12), the product could not be crystallized. 3-~-Keto-y-(~-ni~thyl-2-~yrrolidyl)propyl]-~-qu~nazolone dihydrochloride (IXa). A mixture of 400 mg. of the above rarbethoxy derivative and 5 cc. of 6 ,V hydrochloric acid was refluxed for six hours, then evaporated to dryness zn vacuo and the residue crystallized from absolute alcoholic hydrogen chloride; yield, 250 mg. (625) of Mhite crystals, m.p. 241' dec. Anal. Calc'd for Cl,H1,S302.2HC1.3H?O: C, 52.5; H, 6.06; S , 11.5. Found: C, 52.4; H , 6.39; W, 11.7. h'-(2-Hydroxy-3-methoxypropyl)phthalimide. A mixture of 155 g. of potassium phthalimide, 775 cc. of absolute alcohol, and 115 g. of 2-hydroxy-3-methoxypropylchloride (13) was refluxed and stirred for 16 hours, then diluted mith 1700 cc. of water and extracted twice with chloroform. The combined extracts were evaporated to dryness in vacuo. The residue was dissolved in 300 cc. of benzene a t 25", filtered from phthalimide, and the filtrate evaporaled to dryness zn vacuo; yield, 173 g. (877,), m.p. 60-63". Recrystallization of a sample from heptane containing a little benzene gave white crystals, m.p. 63-64°.2

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B. R. BAKER, R. E. SCHAUB, A S D J. 1%. WILLIAMS

Anal. Calc'd for C12H1&O*: C, 61.3; H, 5.52; N, 5.95. Found: C , 61.4; H, 5.54; N, 6.35. 1-Methory-8-phthalimidoacetone(Ib). To a solution of 135 g. of sodium dichromate dihydrate and 62 cc. of 96y0 sulfuric acid in 720 cc. of water a t 52" was added a warm solution of 153 g. of N-(2-hydroxy-3-methoxypropyl)phthalimide in 500 cc. of acetic acid. The reaction was mildly exothermic and was kept a t 57-60' by occasional cooling for 25 minutes when the temperature began t o drop. After standing for 18 hours, the solution was diluted t o 5 1. with ice-water and cooled in an ice-bath. Filtration gave 64 g. (43%) of product, m.p. 84-86'.

The combined filtrate and washings n-ere extracted twice with chloroform and the extracts evaporated to dryness i n vucuo to give 76 g. of an oil. This was reoxidized as above to give an additional 34 g. (total 65%) of product, m.p. 86-88'. Recrystallization of a sample from aqueous methanol gave white crystals, m.p. 86-87". Anal. Calc'd for C12HI1XO4:C, 61.8; H , 4.i7; N, 6.02. Found: C, 61.8; H, 5.15; S,6.26. The d,4-dinitrophenz~lh~idrazone was recryetallized from benzene-heptane t o give yellow crystals, m.p. 210-211". ,4nal. Calc'd for Cl8H16N507: N, 16.9. Found: K', 17.1. The same yields (two cycles) were obtained when the oxidation was run a t 60" for one hour and the product isolated a t this time. Oxidation a t 80" gave a 49% yield for one cycle. With chromic acid in acetic acid a t 90" for 75 minutes, the oxidation proceeded in only 28% yield for one cycle. Ethyl d-cyano-S-methoxymethyE-~-phthaliinido-2-butenoate (IIb). ,4 mixture of 11.2 g. of I b , 1.5 g. of ammonium acetate, 4.4 cc. of acetic acid, 6 cc. of ethyl cyanoacetate, and 35 cc. of benzene was refluxed under a constant water separator (8) for 14 hours when water separation (1.i cc.) became slow but not complete. The mixture was washed with water and evaporated to dryness i n IJUCUO.Crystallization from alcohol gave 6.5 g. (41%) of product, m.p. 75-80' (turbid). Recrystallization from alcohol gave white crystals of constant m.p. 98-99".

Anal. Calc'd for Cl,HlaNtOs: C, 62.2; H, 4.87; N, 8.54. Found: C, 61.8; H, 5.23; N, 8.50. Longer reflux periods were detrimental to the yield. Ethyl 8-cyano-3-methoxymethyl-4-phthalimidobutyi-ate (IIIb). Hydrogenation of 4 g . of I I b as described for I I a gave 3.3 g. (827,) of product as an oil. Anal. Calc'd for C17H18~205:N, 8.48. Found: N, 8.42. SUMMARY

Synthesis of the mode 1 compound, 3- lo-keto-7-(4-methyl-2-pyrrolidy1)propyll4-quinazolone, starting with either P-methylglutaric acid or phthalimidoacetone has been described via the key intermediates, 3-methyl-4-carbobenzoxyaminobutyric acid and l-carbethoxy-4-methyl-2-pyrrolidineacetic acid. PEARL RIVER,N. Y. REFEREXCES (1) BAKER,QUERRY,POLLIBOFF, SCHAUB,AND WILLIAMS,J . Org. Chem., 17, Paper VI1

of this series. (2) BAKER,SCHAUB, QUERRY, AND WILLIAMS,J . Org. Chem., 17, Paper I X of this series. (3) HIGGINBOTTOM AND LAPWORTH, J. Chem. SOC., 121, 49 (19%). (4) WIDEGVIST,Arch. Kemi, Mineral. Geol., B19, No. 9 (1944); Chem. Abstr., 41, 2693' (1947). (5) STALLBERG-STENHAGEN, Arch. Kemi, Mineral. Geol., %A, S o . 10 (1947); C k m . Abstr. 42. 5851' (1948).

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(6) GABRIEL m a OEHLE,Ber., 50, 804 (1917). ( 7 ) GABRIELAKD PINKUS, Be?., 26, 2197 (1893). ( 8 ) COPE, HOFMAXX, J$'YCKOFF, h V D HARDENBERGH, J . Ant. Chem. S O C . , 63, 3482 (1941). (9) KANEWSKAJA, Ber., 69, 266 (1936). (10) PEARSON, SIGAL,AND KRUG,J . Org. Chem., 15, 1050 (1950). ( G ) BAKER, SCHAUB, QCERRY, AND WILLIAMS, J . Org. Chem., 17, Paper VI11 of this series. (1') BAKER, QCERRY, KADISH,AND ~ ~ I L L I A M I JS ,. o r g . Chem., 17, Paper v of this series. (18) KOELSCII, J . A m . Chein. Soc., 65, 2460 (1943).