The synthesis of some reduced pyrido- and pyrrolo-benzodiazepines

摘要

1972 975The Synthesis of Some Reduced Pyrido- and Pyrrolo-benzodiazepinesBy P. Knowies and K. R. H. Wooldridge, The Research Laboratories, May 8 Baker Ltd., Dagenham, EssexSome 3a-alkyl-2,3,3a,4,5,1O-hexahydro-l H-pyrrolol,2-6 2,4 benzodiazepines and 4a-alkyl-l,2,3,4,4a,5,6.11-octahydropyridol ,2-b 2,4 benzodiazepines have been prepared by reduction of the corresponding 1 -oxo-compounds. The latter were synthesised by the condensation of o-phenylenebismethylamine with the appropriate0x0-ester.FOLLOWING the synthesis of the 1,2,3,4,4a,5,6,11-octa-hydropyrido 1,241 2,4benzodiazepine system (1) ,l wewished to prepare 4a-substituted analogues for pharma-by analogy with the work of Stevenson and Hatt 293who prepared compound (3) by condensation of thediamine with phthalaldehydic acid.It was found thatthe pyrrolodiazepines (4; n = 2) were formed readilyin ethanolic solution but that the pyridodiazepines(4; n = 3) could only be obtained under forcing con-ditions. However, an ester derivative (6) was obtainedH 11) f 2 ) readily from the diamine and the diester (5). Thepyrrolodiazepinones (4a-c) and the pyridodiazepinone0RKICH21n-C02Et(4d) gave the corresponding reduced diazepines (7)on treatment with lithium aluminium hydride.EXPERIMENTAL r: ( 3 ) H IC) 1.r. spectra were determined on a Unicam SP 200 spectro-a ; R = H ,n = 2 Et02Cb ; R = M e , n = 2C: R = E t , n = 2EtO,C (5) d ; R=Me,n = 3'C H -C H 2- C H2- C H 0 /a : R = H , n = 3b : R = Me," = 3c : R = E t , n = 3d R = Me,n = Icological evaluation.The original synthesis was notapplicable and we therefore examined the condensationof ketonic esters (2) with o-phenylenebismethylamine,1 M. Davis, P. Knowles, B. W. Sharp, R. J . A. Walsh, anda H. H. Hatt and E. F. M. Stevenson, J . Chem. Soc., 1952,K. R. H. Wooldridge, J. Chem. Soc. (C), 1971, 2449.199.meter, U.V. spectra on a Unicam SP 700 spectrometer(1 cm cells), IH n.m.r. spectra on a Varian A60-D spectro-meter.o-Phenylenebismethylamine Hydrochloride Hydrate.-Owing to the unsuitability of the literature methods forthe large scale production of the diamine hydrochloridethe following method was devised. Phthalonitrile (300 g)in acetic anhydride (3-5 1) was catalytically hydrogenated(70'; 300 lb in-2; 20 Raney nickel).After uptakehad ceased (92; 4.5 h) excess of solvent was removedila vacuo and the resulting brown oil was heated underreflux with concentrated hydrochloric acid (2-5 1) for 5 h.The acid was removed in vacuo and the residue was dis-solved in water (2 1) and partly clarified with charcoal(2 x 50 g). Removal of the water and trituration with hotethanol (400 ml) gave the diamine hydrochloride (256 g,52) (slow decornp. 3007, identical (i.r. spectrum)with a sample prepared by the literature method (Found:C, 42-7; H, 6-6; N, 12.0. Calc. for C,HI2N,,2HC1,H,O:The free base was liberated by dissolving the diamine3 E. F. M. Stevenson, J. Chem. Soc., 1952, 5024. * H. Strassmann, Ber., 1888, 21, 576.5 E. F. Elslager, D.F. Worth, N. F. Haley, and S. C. Perricone,C, 42-3; H, 7-1; N, 12.3).J . Heterocyclic. Chem., 1968, 5, 609.S. Gabriel and G. Pinkus, Ber., 1893, 26, 2210976 J.C.S. Perkin Ihydrochloride in 10N-sodium hydroxide and continuouslyextracting with ether. This was always carried outimmediately before use, owing to darkening and absorptionof carbon dioxide by the diamine.2,3,3a,4,5,10-Hexahydro- lH-PyrroZo 1,2-b 2,4benzodi-azepin-l-one (4a) .-A mixture of the foregoing diamine(6.8 g) and methyl P-formylpropionate (5.8 g) in dry ethanol(75 ml) was heated under reflux in an atmosphere ofnitrogen for 72 h. The mixture was treated with charcoal,filtered, and concentrated to an oil. Addition of ether(100 ml) afforded the pyrrolodiazepine (5.15 g, 54y0),m.p. 173-175" (from benzene) (Found: 71.3; H, 6.8;N, 13.6.Cl,Hl,N,O requires C, 71.3; H, 7.0; N, 13.9),v,, (KBr) 1670 (GO), 3300 (NH) cm-1, T (10 CDC1,)2-8 (4H, m, ArH), 4.8 and 5-5 (2H, ABq, J 15 Hz, 10-H,),5-08 (lH, t, J 6 Hz, 3a-H), 5.8 (2H, ABq, J 12 Hz, 5-H,),7.7 (3H, m, 2-H, + NH as shown by addition of D,O),and 8-0 (2H, m, 3-H,). The assignment of the two ABquartets is based on the assumption that the diamagneticanisotropy of the carbonyl group would separate thecomponents of the quartet due to the methylene protonsat C-10 to a greater extent than those associated with the5-position.2,4benzodiazepin-l-one (4b) (85), m.p. 171-172", wasprepared similarly from ethyl levulinate (24 h reactionperiod) (Found: C, 72.1; H, 7.4; N, 12-9.Cl,H1,N,Orequires C, 72-2; H, 7.5; N, 13-0y0), vmx. (KBr) 1670(C=O) and 3300 (NH) cm-l, 'c(lOyo CDCl,) 2.8 (4H, m, ArH),5.0 and 5.8 (2H, ABq, J 15 Hz, 10-H,), 6-0 (2H, s, 5-H,),7-8 (5H, m, 2- and 3-H, + NH as shown by addition ofD,O), and 8.4 (3H. s, Me). From the occurrence of asinglet at 'c 6.0 instead of an AB quartet, it is inferred thatthe resonance of the 5-protons are coincident. The re-sonances due to these protons are resolved, however,in the spectrum of the reduction product (7b).3a-Ethyl- 2,3,3a,4,5,1O-hexahydro- 1H-PyrroZo 1,2-b 2,4-benzodiazepin-l-one (4c) (25), m.p. 125-126" frombenzene-petroleum (b.p. 60-80") was prepared similarlyfrom ethyl homolevulinate (24 h reaction period) (Found :C, 73.3; H, 8.0; N, 12.3.Cl,Hl,N,O requires C, 73.1;H, 7.9; N, 12-2y0), v- (KBr) 1660 (GO) and 3300 (NH)cm-l, vmsk (0.03 in CCl,) 1689 (C=O) cm-l, 'c (10 CDC1,)2.85 (4H, m, ArH), 5.1 and 5-95 (2H, ABq, J 15 Hz, 10-H,),6.1 (2H, s, 7.9 (7H, m, 2- and 3-H,, MeCH,, and NH,as shown by addition of D,O), and 9.1 (3H, t, J 6 Hz,CH,*CH,) .1,2,3,4,4a, 5,6,1 l-Octahydro-4a-methyZ~yrido 1 , 2-b 2,4-benzodiazepin-l-one (4d) .-o-Phenylenebismethylamine (25g) and ethyl 5-oxohexanoate (24 g) in 2-ethoxyethanol (250ml) were heated under reflux in an atmosphere of nitrogenfor 72 h. The solvent was removed in vacuo and theresidue was extracted with boiling ether (500 ml). Oncooling, the extract deposited the diazepine (9.0 g, 18),m.p. 134-135" (from benzene-ether) (Found: C, 72.9;H, 8.0; N, 12.2.C14H18N,0 requires C, 73.0; H, 7.9;N, 12.27(0), vmsx. (KBr) 1605 (GO), 3250 (NH) cm-l, v,,(0.03 CC1,) 1640 (GO) cm-l, z (10 CDC1,) 2.65 (4H, m,ArH), 4-65 and 5.4 (2H, ABq, J 16 Hz, 11-H,), 5.75 (2H,ABq, J 17 Hz, 6-H,), 74-7-95 (7H, m, 2-, 3-, and 4-H, andNH as shown by addition of D,O), and 8.3 (3H, s, Me).Ethyl 1,2,3,4,4a,5, 6,l l-Octahydro-l-oxopyrido 1,2-b 2,4-benzodiazepine-2-carboxylate HydrochZoride Hemihydrate (6).-0-Phenylenebismethylamine (1 0 g) and diethyl 3-OXO-propylmalonate (14.2 g) in ethanol (100 ml) were heated2,3,3a,4,5,1O-Hexahydro-3a-methyZ- lH-pyrrolo 1,2,-b-under reflux in an atmosphere of nitrogen for 36 h. Re-moval of the solvent in vucuo and chromatography silicagel (40 x 3 cm) ; acetone of the resulting brown oil gave afraction which after clarification with charcoal and treat-ment with ethereal hydrogen chloride gave the diazepknehydrochzoride (9 g, 37y0), m.p.192-194" Found: C,57.4; H, 6.4; C1, 10.3; N, 8.1; H,O (Karl Fischer) 2.2.Cl,H,oN,0,,HCl,0~5H,0 requires C, 57.6; H, 6.7; C1,10.6; N, 8.4; H,O, 2-7), vmx. (KBr) 1660 (amide GO),1730 (ester GO), 2800, and 2950 (NH2+) cm-l.2,3,3~,4,5,10-Hexahydro- lH-pyrroZo 1,2-b 2,4 benzodi-azepine (7a) .-To a solution of 2,3,3a,4,5,1O-hexahydro-pyrrolo1,2-b2,4benzodiazepin-l-one (1.5 g) in dry ether(40 ml) was added lithium aluminium hydride (0.7 g)during 5 min. The mixture was stirred and refluxed for30 min and the inorganic complex was then decomposed a t-20" with the minimum volume of water.Evaporationof the ethereal extract gave the diazepine (0.8 g, 58y0),m.p. 58-5-60" (from n-pentane at -30") (Found: C,76.7; H, 8-4; N, 14.7. C,,H,,N, requires C, 76-6; H,8.6; N, 14.9y0), v- (KBr) 3250 (NH) cm-l, z (10C,D,) 3.0 (4H, m, ArH), 6.10 and 6.37 (2H, ABq, J 15Hz, 5- or 10-H,), 6-20 and 6.47 (2H, ABq, J 13.4 Hz, 5- or10-H,), 6.6 (lH, t, 3a-H), 7.0-8.8 (7H, m, 1-, 2-, and3-H, NH, as shown by addition of D,O).1,2,3,4,4a,5,6,1 l-Octahydro-4a-methyZpyridol,2-b2,4-benzodiazepine (7d) (46y0), b.p. 160-170' (bulb-to-bulbdistillation at 0.1 mmHg), was prepared similarly (Found :C, 77.4; H, 9-2; N, 13.2. C,,H,,N, requires C, 77.7;H, 9.3; N, 13.0y0), vm, (film) 3300 (NH) cm-l.2,4benzodiazepine (7b) was prepared similarly.Distil-lation of the product b.p. 120-130" (bulb-to-bulb distil-lation at 0.1 mmHg) gave the slightly impure diuzepine(Found: C, 76.7; H, 9-2; N, 13.5. Cl,H18N, requiresC, 77-2; H, 9.0; N, 13.9), vmx. (film) 3300 cm-1, T (10CDCl,) 2.9 (4H, m, ArH), 5-6 (2H, ABq, J 17 Hz, 5- or10-H,), 6.2 (2H, ABq, 5- or 10-H,), 7.4 (2H, m, 1-H,),74-8.5 (5H, m, 2- and 3-H, and NH), and 8-6 (3H, s,Me).Ethereal hydrogenchloride was added and the crude precipitated materialwas decolourised by treatment of a cold aqueous solutionwith charcoal. Removal of solvent at 30" in vacuo gave thediazepine dihydrochloride (65), m.p. 266-267" (softeningat 250") (from ethanol-ether) (Found: C, 55.1; H, 7.3;C1, 25.4; N, 10.2. Cl,H,8N,,2HC1,0~5H,0 requires C,54.9; H, 7.4; C1, 25.0; N, 9.9). Water determinationby the Karl Fischer method was unsatisfactory owing tothe insolubility of the product in the reagent; howeversome water was shown to be present; the i.r. spectrum(KBr) showed multiple peaks at 2400-2900 cm-1 (NH,,NH) .3a-EthyZ-2,3,3a, 4,5,10-hexahydro-lH-pyrroZo 1,2-b 2,4-benzodiazepine (7c) was prepared similarly as its dihydro-chloride hemihydrate (46.5y0), m.p. 248-251' (fromethanol-ether) (Found: C, 56.7; H, 7.6; C1, 23.9; N, 9.1.C,,H2,N,,2HC1,0~5H,0 requires C, 56.4; H, 7.8; C1, 23-8;N, 9.4y0), vmx. (KBr) 2600-2800 cm-l (NH,, NH).2,3,3a,4,5,10-Hexahydro-3a-methyZ-lH-pyrroZol, 2-b-This product was purified as follows.+++ +We thank Mr. T. Threlfall for spectral data, Mr. S. Banceand his staff for microanalyses, and Mr. B. J. V. Mead fortechnical assistance.Received, 1 lth October, 19711 1/185